The Human Transcript Map

A Gene Map of the Human Genome

An update to this work has been released. See GeneMap'99 The Human Genome Project is expected to produce a sequence of DNA representing the
functional blueprint and evolutionary history of the human species Ho!ever" only about #$ of this sequence is thought to specify the portions of our %&"&&& to '&&"&&& genes that encode proteins Thus an important part of basic and applied genomics is to identify and locali(e these genes in a process )no!n as transcript mapping *hen genes are expressed" their sequences are first converted into messenger +NA transcripts" !hich can be isolated in the form of complementary DNAs ,cDNAs- Approximately half of all human genes had been sampled as of '% .une" '//0 A small portion of each cDNA sequence is all that is needed to develop unique gene mar)ers" )no!n as sequence tagged sites or 1T1s" !hich can be detected in chromosomal DNA by assays based on the polymerase chain reaction ,P2+- To construct a transcript map" cDNA sequences from a master catalog of human genes !ere distributed to mapping laboratories in North America" 3urope" and .apan These cDNAs !ere converted to 1T1s and their physical locations on chromosomes determined on one of t!o radiation hybrid ,+H- panels or a yeast artificial chromosome ,4A2- library containing human genomic DNA This mapping data !as integrated relative to the human genetic map and then cross5referenced to cytogenetic band maps of the chromosomes ,6urther details are available in the accompanying article in the 7% 8ctober issue of 1293N23The histograms reflect the distributions and densities of genes along the chromosomes :ecause the individual genes ,;'0"&&&- are too numerous to represent" images have been chosen to illustrate the myriad aspects of human biology" pathology" and relationships !ith other organisms that can be revealed by analysis of genes and their protein products

Featured Genes
'

To see more details on a 6eatured Gene" clic) on the symbol to the left or on the gene symbol 9f your gene of interest is not included on this list" you might find additional medical information in the 8nline <endelian 9nheritence in <an ,8<9<- database" a comphrehensive catalog of human genes and inherited disorders Description Adrenoleu)odystrophy Al(heimer disease" type # Al(heimer disease" type ? Amyotrophic lateral sclerosis Scleroz lateral amiotrofic Apolipoprotein 3 Ataxia telangiectasia :reast cancer" type ' :reast cancer" type 7 :ur)itt lymphoma Limfomul Burkitt 2olon cancer" nonpolyposis" type ' 2olon cancer" nonpolyposis" type 7 2ystic fibrosis Fibroza chistica DiGeorge syndrome
Sindromul DiGeor e Apolipoproteina E

Gene A=D AD# AD? 18D' AP83 AT< :+2A' :+2A7 <42 <1H7 <=H' 26T+ DG1 DTD D<D 3B2 G:A 8AT H+A1 HD 9DD<' =CT' 2DDN7 6:N' ATP@A <3N7A D< N67 8:1

hromosome > '? ' 7' '/ '' '@ '# A 7 # @ 77 % > ? ' '& '' ? 0 '' / '% > '& '/ 77 @ 7

Diastrophic dysplasia Distrofic displazie Duchenne muscular dystrophy Distrofia muscular

Duchenne

3llis5van 2reveld syndrome Sindromul! Gaucher disease Boala Gaucher Gyrate atrophy of the choroid and retina G"rate atrofia
coroidei #i retinei

Harvey ras oncogene Har$e" ras onco ene ale

papilloma$irusului

Huntington disease Bolii Huntin ton .uvenile onset diabetes Debut diabet %u$enil =ong CT syndrome Sindromul &' lun <alignant melanoma Melanomul mali n <arfan syndrome Sindromul Marfan <en)es syndrome Sindromul Menkes <ultiple endocrine neoplasia (eoplazie endocrine multiple <yotonic dystrophy M"otonic distrofia Neurofibromatosis" type 7 (eurofibromatoza) de tip * 8besity

Phenyl)etonuria Fenilcetonurie Polycystic )idney disease +inichi polichistic +etinoblastoma" type ' +etinoblastomului) tip , 1evere combined immunodeficiency 1mall cell lung carcinoma -arcinom pulmonar cu celule
mici

PAH PDD' +:' ADA 12=2' 12A' 1+D%A' DP2? TD6 T12' BH= PA># *+N ATP@: 6<+' P>+'

'7 '0 '# 7& # 0 % 'A 4 / '@ # 7 A '# > '7

1pinocerebellar atrophy Spinocerebelar atrofia 1teroid %5alpha5reductase5' Steroizi ./alfa/reductaza/, 1uppressor of pancreatic carcinoma Supresoare de
carcinom pancreatic

Testis5determining factor Factor de testicul/determinarea Tuberous sclerosis

Scleroza tuberoasa

Tumor suppressor protein p%# 'umora supresoare prot0 p.1 TP%# Bon Hippel5=indau syndrome *aardenberg syndrome *erner syndrome *ilson disease >5lin)ed mental retardation Eell!eger syndrome

A!D " Adrenoleukod#stroph# Adrenoleu)odystrophy ,A=D- is a rare" inherited metabolic disorder that afflicts the young
boy =oren(o 8done" !hose story is told in the '//# film F=oren(oFs oilF 9n this disease the fatty covering ,myelin sheath- on nerve fibers in the brain is lost" and the adrenal gland degenerates" leading to progressive neurological disability and death People !ith A=D accumulate high levels of saturated" very long chain fatty acids in their brain and adrenal cortex because the fatty acids are not bro)en do!n by an en(yme in the normal manner 1o" !hen the A=D gene !as discovered in '//#" it !as a surprise that the corresponding protein !as in fact a member of a family of transporter proteins" not an en(yme 9t is still a mystery as to ho! the transporter effects the function the fatty acid en(yme" and for that matter" ho! high levels of very long chain fatty acids cause the loss of myelin on nerve fibers <ore recently" all the transporters related to A=D protein have been found in the yeast 1accharomyces cerevisiae" and a mouse model for the human disease has been developed These and other molecular biology approaches should further our understanding of A=D and hasten our progress to!ards effective therapies $f %ote A=D !as the illness afflicting young =oren(o 8done of <aryland" !hose story !as the basis of the film" G=oren(oFs 8il"G starring 1usan 1arandon and Nic) Nolte

hromosome &

DMD Defects in the dystrophin gene cause Duchenne muscular dystrophy" a fatal progressive degeneration of muscle tissue IMAGE CREDIT: R. Worton, Ottawa General Hospital, Ottawa, CANADA. Adapted for SCIENCE ! ". S#tliff.

AT'(A Abnormal Pur)inje cell dendrites in the brain of a patient !ith <en)es disease IMAGE CREDIT: "e$in Rot% and Ro ert S&%'idt, Was%in(ton )ni$ersit!, St. *o#is, MO, )SA

FM)* An unstable nucleotide repeat is associated !ith the most common form of mental retardation )no!n as 6ragile > syndrome

AD+ " Al,heimer's Disease Al(heimerFs disease ,AD- is the fourth leading cause of death in adults
The incidence of the disease rises steeply !ith age AD is t!ice as common in !omen than in men" although ex5 president +onald +eagan is a !ell )no!n disease sufferer 1ome of the most frequently observed symptoms of the disease include a progressive inability to remember facts and events and" later" to recogni(e friends and family AD tends to run in familiesH currently" mutations in four genes" situated on chromosomes '" '?" '/ and 7'" are believed to play a role in the disease The formation of lesions made of fragmented brain cells surrounded by amyloid5family proteins are characteristic of the disease 9nterestingly" these lesions and their associated proteins are closely related to similar structures found in Do!nFs 1yndrome Tangles of filaments largely made up of a protein ?

associated !ith the cytos)eleton have also been observed in samples ta)en from Al(heimerFs brain tissue 2urrently" scientists are studying the interrelationship bet!een the various gene loci ,particularly the mutation on chromosome 7'-" and ho! environmental factors could effect a personFs susceptibility to AD +ecently" use of a mouse model of the disease identified an en(yme that may be responsible for the increase in amyloid production characteristic of AD 9f a !ay to regulate this en(yme could be found" then AD may be slo!ed or halted in some people

hromosome *-

AD+ Neuritic plaques and neurofibrillary tangles are the major microscopic abnormalities in the brains of patients !ith Al(heimerFs disease IMAGE CREDIT: +atri&, M&Geer, )ni$ersit! of -ritis% Col#' ia, -.C., CANADA.

AD- " Al,heimer's Disease Al(heimerFs disease ,AD- is the fourth leading cause of death in adults
The incidence of the disease rises steeply !ith age AD is t!ice as common in !omen than in men" although ex5 president +onald +eagan is a !ell )no!n disease sufferer 1ome of the most frequently observed symptoms of the disease include a progressive inability to remember facts and events and" later" to recogni(e friends and family AD tends to run in familiesH currently" mutations in four genes" situated on chromosomes '" '?" '/ and 7'" are believed to play a role in the disease The formation of lesions made of fragmented brain cells surrounded by amyloid5family proteins are characteristic of the

disease 9nterestingly" these lesions and their associated proteins are closely related to similar structures found in Do!nFs 1yndrome Tangles of filaments largely made up of a protein associated !ith the cytos)eleton have also been observed in samples ta)en from Al(heimerFs brain tissue 2urrently" scientists are studying the interrelationship bet!een the various gene loci ,particularly the mutation on chromosome 7'-" and ho! environmental factors could effect a personFs susceptibility to AD +ecently" use of a mouse model of the disease identified an en(yme that may be responsible for the increase in amyloid production characteristic of AD 9f a !ay to regulate this en(yme could be found" then AD may be slo!ed or halted in some people

hromosome *

G.A 9n Gaucher disease" the defective en(yme is unable to metaboli(e glucocerebrosides !hich accumulate in characteristic" distended phagocytic cells IMAGE CREDIT: E. -e#tler, S&ripps Resear&% Instit#te, *a .olla, CA, )SA

AD- :rain scans of a healthy elderly person and a patient !ith Al(heimerFs disease

S$D * " Am#otrophic !ateral Sclerosis /A!S01 2!ou Gehri3's Disease2

Amyotrophic lateral sclerosis ,A=1- is a neurological disorder characteri(ed by progressive degeneration of motor neuron cells in the spinal cord and brain" !hich ultimately results in paralysis and death The disease ta)es its less5 scientific name from =ou Gehrig" a baseball player !ith the Ne! 4or) 4an)ees in the late '/7&s and '/#&s" !ho !as forced to retire in '/#/ as a result of the loss of motor control caused by the disease 9n '//'" a team of researchers lin)ed familial A=1 to chromosome 7' T!o years later" the gene associated !ith A=1" 18D'" !as identified as being associated !ith many cases of familial A=1 The en(yme coded for by 18D' carries out a very important function in cellsH it removes dangerous superoxide radicals by converting them into non5harmful substances Defects in the action of this en(yme mean that the superoxide radicals attac) cells from the inside" causing their death 1everal different mutations in this en(yme all result in A=1" ma)ing the exact molecular cause of the disease difficult to ascertain +ecent research has suggested that treatment !ith drugs called anti5oxidants may benefit A=1 patients Ho!ever" since the molecular genetics of the disease are still unclear" a significant amount of research is still required to design other promising treatments for A=1

hromosome 4*

S$D* Amyotrophic lateral sclerosis" also )no!n as =ou GehrigFs disease" is caused in some cases by a deficiency in the en(yme superoxide dism

A'$5 " Apolipoprotein 5 Atherosclerosis is a disease that can affect people at any age" although it usually doesnFt pose
a threat until people reach their forties or fifties 9t is characteri(ed by a narro!ing of the arteries caused by cholesterol5rich plaques of immune5system cells Dey ris) factors for atherosclerosis" !hich can be genetic andIor environmental" includeH elevated levels of cholesterol and triglyceride in the blood" high blood pressure and cigarette smo)e

A protein called apolipoprotein 3" !hich can exist in several different forms" is coded for by a gene found on chromosome '/ 9t is important for removing excess cholesterol from the blood" and does so by carrying cholesterol to receptors on the surface of liver cells Defects in apolipoprotein 3 sometimes result in its inability to bind to the receptors" !hich leads to an increase a personFs blood cholesterol" and consequently their ris) of atherosclerosis 2urrently" a debate is raging over ho! the various mutated forms of apolipoprotein 3 effect the body As a result" many of the treatments proposed remain in their experimental phase *hile mice are proving useful for modeling the human disease" a great deal of research is still required before !e can fully understand the mechanisms that regulate the levels of lipoproteins 5 li)e apolipoprotein 3 5 in the blood

hromosome *9

A'$5 Atherosclerotic coronary artery disease is associated !ith the gene encoding apolipoprotein 3" a ligand for the =D= receptor

DM <yotonic dystrophy is a muscular disease associated !ith an unstable nucleotide repeat that is amplified bet!een generations

ATM " Ata6ia Telan3iectasia

Ataxia telangiectasia ,A5T- is a progressive" degenerative disease characteri(ed by cerebellar

degeneration ,the cerebellum is the small fissured mass at the base of the brain" behind the brain stem-" immunodeficiency" radiosensitivity ,sensitivity to radiant energy" such as x5ray-" and predisposition to cancer 9t affects a startling variety of bodily systems A5T children appear normal at birth" and the first signs of disease usually appear during the second year of life These first clues are usually a G!obblyG lac) of balance and slurred speech caused by ataxia" !hich means Ga lac) of muscle control G The cerebellum is the part of the brain that controls movement *hen it begins to degenerate" there is a gradual loss of muscle control in the patient !hich eventually confines him or her to a !heelchair :ecause of the !orsening ataxia" A5T children lose their ability to !rite and speech also becomes slo!ed and slurred 3ven reading eventually becomes impossible" as eye movements become difficult to control 1oon after the onset of the ataxia" the patient usually sho!s another clinical hallmar) of A5TH GtelangiectasiasG or tiny red GspiderG veins !hich appear in the corners of the eyes or on the surface of the ears and chee)s Although these telangiectasias are harmless" their unique appearance" together !ith ataxia" is !hat led to giving the disease its name <ost ,about A&$ of- children !ith A5T suffer from immunodeficiency that brings about recurrent respiratory infections 9n many patients" these infections can become life5 threatening 6or these A5T patients" the combination of a !ea)ened immune system and the progressive ataxia can ultimately lead to pneumonia as a common cause of death 2hildren !ith A5T tend to develop malignancies of the blood system almost '"&&& times more frequently than the general population =ymphomas and leu)emias are particularly common types of cancer" although the frequencies of most cancers are elevated 9ronically" because most A5T patients are extremely sensitive to radiation" they cannot tolerate the therapeutic radiation usually given to cancer patients A5T cuts across the !hole spectrum of race" geography and socioeconomic level <ales and females are equally affected 3pidemiologists estimate that A5T stri)es bet!een ' in ?&"&&& to ' in '&&"&&& births Ho!ever" itFs believed that many A5T children" particularly those !ho die at a young age" are never properly diagnosed" so the disease may actually be much more common There is presently no cure for A5T but ne! treatments to alleviate the symptoms are being developed Physical" occuaptional and speech therapy are used to help maintain flexibility" gamma5globulin injections help supplement the immune systems of A5T patients" and high5 dose vitamin regimes are being underta)en !ith moderate success

'&

hromosome **

!7T* Portion of an 3DG used to diagnose long5CT syndrome" an inherited cardiac arrythmia associated !ith mutations in an ion channel protein IMAGE CREDIT: .o%n T. Co&,er%a', Geor(etown )ni$ersit! Medi&al Center, Was%in(ton DC, )SA.

H)AS Three5dimensional structure of +as" the product of an oncogene that is mutated in many human cancers

.) A* " .reast ancer :reast cancer is often detected !hen there are visible changes in the breast" such as a lump"
thic)ening" s!elling" dimpling" s)in irritation" distortion" retraction" scaliness" pain" tenderness of the nipple" or nipple discharge :reast cancer is the second major cause of cancer death in American !omen An estimated ??"%0& lives ,??"#&& !omen and 70& men- !ill be lost to breast cancer in the J 1 in '//0 About 'A?"#&& ne! invasive cases among !omen !ill be diagnosed this year About '"?&& ne! cases of breast cancer !ill be diagnosed among American men during this same period :reast cancer incidence rates among !omen increased about ? &x& &&&&&&&%'%@ap5'&77 year bet!een '/A7 and '/A@" but recently leveled off at about ''& cases per '&&"&&& <ost of the recent increase in rates is believed to be due to mar)ed increases in mammography use" ''

allo!ing the detection of early5stage breast cancers" frequently before they become clinically apparent The ris) of breast cancer increases !ith age The ris) is higher in a !oman !ho hasH a personal or family history of breast cancerK some forms of benign breast diseaseK an early beginning of menstruationK late menopauseK lengthy exposure to cyclic estrogenK never had children" or had the first live birth at a later ageK lo!er socioeconomic status and lo!er education level To date" )no!ledge about ris) factors has not translated into practical !ays to prevent breast cancer 1ince !omen may not be able to alter their personal ris) factors" the best opportunity at present for reducing mortality is through early detection 9tFs recommended that asymptomatic !omen aged ?&5?/ should have a screening mammogram every '57 yearsK and !omen aged %& and over" every year 9n addition" a clinical breast exam is recommended every three years for !omen 7&5?&" and every year for !omen over ?& Ta)ing into account the medical situation and the patientFs preferences" treatment may involve lumpectomy ,local removal of the tumor-" mastectomy ,surgical removal of the breast-" radiation therapy" chemotherapy" or hormone therapy 8ften" t!o or more methods are used in combination 9n recent years" ne! techniques have made breast reconstruction possible after mastectomy" and the cosmetic results are usually good +econstruction has become an important part of treatment and rehabilitation

hromosome *(

T'8+ 4ello! dots indicate some of the many types of tumors that carry mutations in the p%# gene

.) A* Distribution of mutations in the :+2A' gene !ich is associated !ith early5onset breast and ovarian cancer cance

'7

.) A4 " .reast ancer :reast cancer is often detected !hen there are visible changes in the breast" such as a lump"
thic)ening" s!elling" dimpling" s)in irritation" distortion" retraction" scaliness" pain" tenderness of the nipple" or nipple discharge :reast cancer is the second major cause of cancer death in American !omen An estimated ??"%0& lives ,??"#&& !omen and 70& men- !ill be lost to breast cancer in the J 1 in '//0 About 'A?"#&& ne! invasive cases among !omen !ill be diagnosed this year About '"?&& ne! cases of breast cancer !ill be diagnosed among American men during this same period :reast cancer incidence rates among !omen increased about ? &x& &&&&&&&%'%@ap5'&77 year bet!een '/A7 and '/A@" but recently leveled off at about ''& cases per '&&"&&& <ost of the recent increase in rates is believed to be due to mar)ed increases in mammography use" allo!ing the detection of early5stage breast cancers" frequently before they become clinically apparent The ris) of breast cancer increases !ith age The ris) is higher in a !oman !ho hasH a personal or family history of breast cancerK some forms of benign breast diseaseK an early beginning of menstruationK late menopauseK lengthy exposure to cyclic estrogenK never had children" or had the first live birth at a later ageK lo!er socioeconomic status and lo!er education level To date" )no!ledge about ris) factors has not translated into practical !ays to prevent breast cancer 1ince !omen may not be able to alter their personal ris) factors" the best opportunity at present for reducing mortality is through early detection 9tFs recommended that asymptomatic !omen aged ?&5?/ should have a screening mammogram every '57 yearsK and !omen aged %& and over" every year 9n addition" a clinical breast exam is recommended every three years for !omen 7&5?&" and every year for !omen over ?& Ta)ing into account the medical situation and the patientFs preferences" treatment may involve lumpectomy ,local removal of the tumor-" mastectomy ,surgical removal of the breast-" radiation therapy" chemotherapy" or hormone therapy 8ften" t!o or more methods are used in combination 9n recent years" ne! techniques have made breast reconstruction possible after mastectomy" and the cosmetic results are usually good +econstruction has become an important part of treatment and rehabilitation

hromosome *+

.) A4 <ammogram sho!ing breast cancer

'#

).* 2hildhood tumors of the retina are associated !ith inactivation of the retinoblastoma gene

AT'(. 9n *ilsonFs disease" toxic levels of copper accumulate and damage many tissues and organs" including the basal ganglia of the brain

M9 : " .urkitt's !#mphoma :ur)ittFs lymphoma is a rare form of cancer predominantly affecting young children in
central Africa" but the disease has also been reported in other areas 9t is manifested most often as a large lesion in the ja! and expands rapidly over a period of a fe! !ee)s to invade the orbit ,the bony cavity containing the eyeball- 9t may occasionally spread to other parts of the head as !ell Bisceral involvement" usually an abdominal mass" is common The bone marro! and central nervous system may be involved and this !orsens the prognosis :ur)ittFs lymphoma patients display abnormal protrusion of the eyeballs and gross facial s!elling Diagnosis is made by incisional biopsy Treatment of the ja! and eye areas is by radiotherapy" !hile visceral involvement requires systemic chemotherapy 2entral nervous system involvement calls for a combination of both types of treatment A reciprocal chromosome translocation in;ol;in3 the c"m#c onco3ene is associated with .urkitt l#mphoma

'?

IMAGE CREDIT: Gre(or! S&%#ler, NC-I, NIH, -et%esda, MD, )SA.

hromosome :

<)% *ernerFs syndrome is a disease of premature and accelerated aging associated !ith defects in a DNA un!inding en(yme IMAGE CREDIT: Willia' and Wil,ens +# lis%in( Co.

M9 A reciprocal chromosome translocation involving the c5myc oncogene is associated !ith :ur)itt lymphoma

MSH4 " olon ancer1 nonpol#posis1 t#pe *

'%

The American 2ancer 1ociety estimates that there !ill be /?"'&& ne! cases of colon cancer
diagnosed in the J1 in '//@" !ith ?0"0&& resulting deaths All )inds of cancer occur !hen cell division" normally a very highly regulated process" gets out of control *hile environmental factors can certainly contribute to a personFs ris) of cancer ,e g smo)ing" diet and exercise-" most cancers have a genetic basis too =iterally hundreds of genes and proteins are involved in monitoring the process of cell division and DNA replicationK a mutation in one or more of these genes or proteins can sometimes lead to uncontrolled cancerous gro!th 2olon cancer is one of the most common inherited cancer syndromes )no!n T!o )ey genes involved in colon cancer have been foundH <1H7" on chromosome 7 and <=H'" on chromosome # Normally" the protein products of these genes help to repair mista)es made in DNA replication 9f the <1H7 and <=H' proteins are mutated and therefore donFt !or) properly" the replication mista)es are not repaired" leading to damaged DNA and" in this case" colon cancer Developing diagnostics for colon cancer based on these genes is li)ely to be complex" since there are many mutations )no!n Ho!ever" studies on the equivalent genes in mice and bre!erFs yeast are helping to further our understanding of the mechanisms of DNA repair" and the role that environmental factors might play in colon cancer incidence

hromosome 4

MSH4 A human gene mutated in some colon cancers is homologous to an en(yme in the DNA mismatch repair path!ay in bacteria

'A&+ Portion of a pedigree of *aardenburg syndrome" indicating the occurrence of deafness and changes in pigmentation" including a !hite foreloc

'0

M!H* " olon ancer1 nonpol#posis1 t#pe 4 The American 2ancer 1ociety estimates that there !ill be /?"'&& ne! cases of colon cancer
diagnosed in the J1 in '//@" !ith ?0"0&& resulting deaths All )inds of cancer occur !hen cell division" normally a very highly regulated process" gets out of control *hile '@

environmental factors can certainly contribute to a personFs ris) of cancer ,e g smo)ing" diet and exercise-" most cancers have a genetic basis too =iterally hundreds of genes and proteins are involved in monitoring the process of cell division and DNA replicationK a mutation in one or more of these genes or proteins can sometimes lead to uncontrolled cancerous gro!th 2olon cancer is one of the most common inherited cancer syndromes )no!n T!o )ey genes involved in colon cancer have been foundH <1H7" on chromosome 7 and <=H'" on chromosome # Normally" the protein products of these genes help to repair mista)es made in DNA replication 9f the <1H7 and <=H' proteins are mutated and therefore donFt !or) properly" the replication mista)es are not repaired" leading to damaged DNA and" in this case" colon cancer Developing diagnostics for colon cancer based on these genes is li)ely to be complex" since there are many mutations )no!n Ho!ever" studies on the equivalent genes in mice and bre!erFs yeast are helping to further our understanding of the mechanisms of DNA repair" and the role that environmental factors might play in colon cancer incidence

hromosome +

=H! <icroscopic section of hemangioblastoma" a tumor of the cerebellum characteri(tically found in patients !ith von Hippel5 =indau disease IMAGE CREDIT: "e$in Rot% and Ro ert S&%'idt, Was%in(ton )ni$ersit!, St. *o#is, MO, )SA

S ! * Deletion of a tumor suppressor gene is associated 'A

!ith one type of lung cancer A large tumor ,2a- of the lung is visible in this 2T scan IMAGE CREDIT: +at Connell!, Mia'i /alle! Hospital, Da!ton, OH, )SA

M!H* 6or this gene" as for <1H7" homologies to genes in DNA repair path!ays in model organisms such as yeast shed light on human pathology

FT) " #stic Fibrosis 2ystic fibrosis ,26- is the most common fatal genetic disease in the J1 today
9t causes the body to produce a thic)" stic)y mucus that clogs the lungs" leading to infection" and bloc)s the pancreas" stopping digestive en(ymes from reaching the intestines !here they are required to digest food 26 is caused by a defective gene" !hich codes for a sodium and chloride ,salt- transporter found on the surface of the epithelial cells that line the lungs and other organs 1everal hundred mutations have been found in this gene" all of !hich result in defective transport of sodium and chloride by epithelial cells The severity of the disease symptoms of 26 is directly

'/

related to the characteristic effects of the particular mutation,s- that have been inherited by the sufferer 26 research has accelerated sharply since the discovery of 26T+ in '/A/ 9n '//&" scientists successfully cloned the normal gene and added it to 26 cells in the laboratory" !hich corrected the defective sodium chloride transport mechanism This technique 5 gene therapy 5 !as then tried on a limited number of 26 patients Ho!ever this treatment may not be as successful as originally hoped 6urther research !ill be required before gene therapy" and other experimental treatments" prove useful in combating 26

hromosome (

FT) The gene encoding a chloride ion channel is defective in patients !ith cystic fibrosis IMAGE CREDIT: 0. Alaw1ati, Col#' ia )ni$ersit!, N2, )SA. Adapted ! ". S#tliff, SCIENCE.

$.S The obese ,8bmutation in the mouse provides a useful model system for studying human obesity Reprinted fro' SCIENCE.

7&

DGS " DiGeor3e S#ndrome DiGeorge syndrome is a rare congenital ,i e

present at birth- disease !hose symptoms vary greatly bet!een individuals" but commonly include a history of recurrent infection" heart defects and characteristic facial features DiGeorge syndrome is caused by a large deletion from chromosome 77" produced by an error in recombination at meiosis ,the process that creates germ cells and ensures genetic variation in the offspring- This deletion al!ays includes the DiGeorge syndrome gene 5 DG1 5 and often other genes as !ell 9t appears that the variation in the symptoms of the disease is related to the amount of genetic material lost in addition to the DG1 gene Although researchers no! )no! that the DG1 gene is required for the normal development of the thymus and related glands" counteracting the loss of DG1 is difficult 1ome effects" for example" the cardiac problems and some of the speech impairments" can be treated either surgically or therapeutically" but the loss of immune5system T5cells ,produced by the thymusis more challenging" and requires further research on recombination and immune function Deletion of 3enes in DiGeor3e s#ndrome is ;isuali,ed b# a fluorescent si3nal on onl# one of the two copies of chromosome 44

IMAGE CREDIT: Da$id Ian Wilson, )ni$ersit! of New&astle #pon T!ne, )"

hromosome 44

7'

DGS Deletion of genes in DiGeorge syndrome is visuali(ed by a fluorescent signal on only one of the t!o copies of chromosome 77 IMAGE CREDIT: Da$id Ian Wilson, )ni$ersit! of New&astle #pon T!ne, )"

%F4 <icroscopic section of a sch!annoma" a tumor commonly found in patients !ith neurofibromatosis" type 7

DTD " Diastrophic D#splasia Diastrophic dysplasia ,DTD- is a rare gro!th disorder in !hich patients are usually short"
have club feet and have malformed hands and joints Although found in all populations" it is particularly prevalent in 6inland The gene !hose mutation results in DTD maps to chromosome % and encodes a novel sulfate transporter This ties in !ith the observation of unusual concentrations of sulfate in various tissues of DTD patients 1ulfate is important for s)eletal joints because cartilage 5 the shoc)5 absorber of joints 5 requires sulfur during its manufacture Adding sulfur increases the negative charge !ithin cartilage" !hich contributes to its shoc)5absorbing properties A great deal of further research must be done before this condition is fully understood and effective therapies are developed

77

)adio3raph of the hand of a patient with diastrophic d#splasia

hromosome 8

DTD +adiograph of the hand of a patient !ith diastrophic dysplasia" caused by mutations in a gene encoding a sulfate transport protein IMAGE CREDIT: Eri& *ander, W%ite%ead Instit#te, MIT, Ca' rid(e, MA, )SA

S)D8A* Discovery of the plant homolog of human steroid %5alpha reductase lin)s botany to endocrinology and may lead to ne! d

DMD " Duchenne Muscular D#stroph#

Duchenne muscular dystrophy ,D<D- is one of a group of muscular dystrophies 7#

characteri(ed by enlargement ,pseudohypertrophy- of muscles All are >5lin)ed and affect mainly males ,GDystrophyG refers to any of a number of disorders characteri(ed by !ea)ening" degeneration or abnormal development of muscle D<D is one of the most prevalent types of muscular dystrophy The disorder is characteri(ed by rapid progression of muscle degeneration !hich occurs early in life

hromosome &

DMD Defects in the dystrophin gene cause Duchenne muscular dystrophy" a fatal progressive degeneration of muscle tissue IMAGE CREDIT: R. Worton, Ottawa General Hospital, Ottawa, CANADA. Adapted for SCIENCE ! ". S#tliff.

7?

AT'(A Abnormal Pur)inje cell dendrites in the brain of a patient !ith <en)es disease

FM)* An unstable nucleotide repeat is associated !ith the most common form of mental retardation )no!n as 6ragile > syndrome

A!D <ylein5stained section of brain in adrenoleu)odystrophy" characteri(ed by defective catabolism of long chain fatty acids

5= " 5llis";an re;eld S#ndrome

3llis5van 2reveld syndrome" also )no!n as Gchondroectodermal dysplasia"G is a rare genetic disorder characteri(ed by short limb d!arfism" additional fingers andIor toes ,polydactyly-" abnormal development of the fingernails and" in over half of cases" congenital heart defects

7%

9n addition" there may be changes in the upper lip ,partial harelip or lip" for example- This disorder is inherited through an autosomal ,refers to the autosomes" any ordinary paired chromosomes ali)e in males and females-" recessive trait ,A recessive trait is incapable of expression unless the responsible gene is carried by both members of a pair of homologous chromosomes 3llis5van 2reveld has an unusually high incidence among the 8ld 8rder Amish community in =ancaster 2ounty" Pennsylvania This inbred" isolated religious group has been carefully studied" as it affords a rare opportunity to observe the passage of this particular disorder from generation to generation

hromosome -

HD :rain section from a patient !ith HuntingtonFs disease sho!ing dilatation of ventricles and atrophy of caudate nucleus

5= 3llis5van 2reveld syndrome ,six5fingered d!arfism- has increased prevalence in the 8ld 8rder Amish community

G.A " Gaucher Disease

70

Gaucher ,pronounced Ggo51HA4G- disease is an inherited illness caused by a gene

mutation Normally" this gene is responsible for an en(yme called glucocerebrosidase that the body needs to brea) do!n a particular )ind of fat called glucocerebroside 9n people !ith Gaucher disease" the body is not able to properly produce this en(yme and the fat cannot be bro)en do!n 9t then accumulates" mostly in the liver" spleen and bone marro! Gaucher disease can result in pain" fatigue" jaundice" bone damage" anemia and even death Gaucher disease is considerably more common in the descendants of .e!ish people from eastern 3urope ,Ash)ena(i-" although individuals from any ethnic group may be affected Among the Ash)ena(i .e!ish population" Gaucher disease is the most common genetic disorder" !ith an incidence of approximately ' in ?%& persons 9n the general public" Gaucher disease affects approximately ' in '&&"&&& persons According to the National Gaucher 6oundation" 7"%&& Americans suffer from Gaucher disease 9n '//'" en(yme replacement therapy became available as the first effective treatment for Gaucher disease The treatment consists of a modified form of the glucocerebrosidase en(yme given intravenously Performed on an outpatient basis" the treatment ta)es about '57 hours and is given every 7 !ee)s 3n(yme replacement therapy can stop and often reverse the symptoms of Gaucher disease" allo!ing patients to enjoy a better quality of life

hromosome *

G.A 9n Gaucher disease" the defective en(yme is unable to metaboli(e glucocerebrosides !hich accumulate in characteristic" distended phagocytic cells IMAGE CREDIT: E. -e#tler, S&ripps Resear&% Instit#te, *a .olla, CA, )SA

7@

AD- :rain scans of a healthy elderly person and a patient !ith Al(heimerFs disease

7A

$AT " G#rate Atroph# of the horoid and )etina People suffering from gyrate atrophy of the choroid ,the thin coating of the eye- and retina
face a progressive loss of vision" !ith total blindness usually occurring bet!een the ages of ?& and 0& The disease is an inborn error of metabolism The gene !hose mutation causes gyrate atrophy is found on chromosome '&" and encodes an en(yme called ornithine )etoacid aminotransferase ,8AT- Different inherited mutations in 8AT cause differences in the severity of symptoms of the disease 8AT converts the amino acid ornithine from the urea cycle ultimately into glutamate 9n gyrate atrophy" !here 8AT function is affected" there is an increase in plasma levels of ornithine 9t is already )no!n that reduction of the amino acid arginine in the diet has a salutary effect on most patients 2urrent lines of research into the disease includeH ,'- investigating ho! varient mutations of the alleles ,versions of the gene inherited- interact in order to cause the differing symptoms of the disease and ,7- !or) on mouse models of the disease is furthering our understanding" !hich is hoped !ill lead to a true cure The retina of a patient with 3#rate atroph# of the choroid and retina of the e#e caused b# ornithine aminotransferase deficienc#

hromosome *>

M5%4A The syndrome of multiple endocrine neoplasia ,type 7A- is characteri(ed by

7/

tumors in the thyroid" parathyroid and adrenal glands IMAGE CREDIT: ". S#tliff, SCIENCE.

$AT The retina of a patient !ith gyrate atrophy of the choroid and retina of the eye caused by ornithine aminotransferase deficiency

H)AS " Har;e# )AS $nco3ene

Three5dimensional structure of +as" the product of an oncogene that is mutated in many human cancers The H)AS 3ene maps to chromosome **

Database )ecords H+A1 entry in 8<9<

#&

hromosome **

!7T*. 'ortion of an 5?G used to dia3nose lon3"7T s#ndrome1 an inherited cardiac arr#thmia associated with mutations in an ion channel protein @MAG5 )5D@TA Bohn T. ockerham1 Geor3etown Cni;ersit# Medical enter1 <ashin3ton D 1 CSA.

H)AS. Three" #'

dimensional structure of )as1 the product of an onco3ene that is mutated in man# human cancers @MAG5 )5D@TA Mark .o3uski1 % .@1 %@H1 .ethesda1 MD1 CSA

ATM. Ata6ia" telan3iectasia is multi" s#stem disease characteri,ed b# cerebellar de3eneration1 immunodeficienc# and predisposition to cancer

HD " Huntin3ton's Disease HuntingtonFs disease ,HD- is an inherited" degenerative neurological disease that leads to
dementia About #&"&&& Americans have HD and about '%&"&&& more are at ris) of inheriting the disease from a parent The HD gene" !hose mutation results in HuntingtonFs disease" !as mapped to chromosome ? in '//# The mutation is a characteristic expansion of a nucleotide triplet repeat in the DNA that codes for the protein huntingtin The number of repeated triplets 5 2AG ,cytosine" adenine" guanine- 5 increases !ith the age of the patient 1ince people !ho have those repeats al!ays suffer from HuntingtonFs disease" it suggests that the mutation causes a gain5of5 function" in !hich the m+NA or protein ta)es on a ne! property or is expressed inappropriately *ith the discovery of the HD gene" a ne! predictive test !as developed that allo!s those at ris) to find out !hether or not they !ill develop the disease Animal models have also been developed" and !e )no! that mice have a gene that has the exact function as the human HD gene +esearch on understanding the mechanism that causes the triplet repeat to increase is ongoing" since its discovery could be critical to the development of an effective treatment for this and other similar diseases

hromosome -

#7

HD :rain section from a patient !ith HuntingtonFs disease sho!ing dilatation of ventricles and atrophy of caudate nucleus IMAGE CREDIT: "e$in Rot% and Ro ert S&%'idt, Was%in(ton )ni$ersit!, St. *o#is, MO, )SA

5= 3llis5van 2reveld syndrome ,six5fingered d!arfism- has increased prevalence in the 8ld 8rder Amish community

@DDM* " Bu;enile $nset Diabetes Diabetes is a chronic metabolic disorder that adversely affects the bodyFs ability to
manufacture and use insulin" a hormone necessary for the conversion of food into energy The disease greatly increases the ris) of blindness" heart disease" )idney failure" neurological disease and other conditions for the approximately '0 million Americans !ho are affected by it Type 9" or juvenile onset diabetes" is the more severe form of the illness 9t is no! )no!n that increased ris) for Type 9 diabetes is related to a mutation in the insulin5 dependent diabetes mellitus ,9DD<'- gene on chromosome 0 3xactly ho! this mutation ##

adds to patient ris) is not clear" although the gene maps to the region of chromosome 0 that also has genes for antigens ,the molecules that normally tell the immune system not to attac) itself- 9n Type 9 diabetes" the bodyFs immune system mounts an immunological assault on its o!n insulin and the pancreatic cells that manufacture it Ho!ever" the mechanism of ho! this happens is not yet understood 2onscientious patient care and daily insulin dosages can )eep patients comparatively healthy :ut in order to prevent the immunoresponses that often cause diabetes" !e !ill need to experiment further !ith mouse models of the disease" and advance our understanding of ho! genes on other chromosomes might add to a patientFs ris) of diabetes

hromosome D

S A* Degeneration of the cerebellum leads to loss of muscle coordination in patients !ith spinocerebellar atrophy IMAGE CREDIT: "e$in Rot% and Ro ert S&%'idt, Was%in(ton )ni$ersit!, St. *o#is, MO, )SA.

@DDM* .uvenile onset diabetes" in !hich the bodyFs o!n T lymphocytes infiltrate and destroy insulin5producing pancreatic islet cells" is associated !ith the major histocompatibility complex

!7T* " !on3"7T S#ndrome

#?

=ong5CT syndrome ,=CT1- results from structural abnormalities in the potassium channels
of the heart" !hich predispose affected persons to an accelerated heart rhythm ,arrhythmiaThis can lead to sudden loss of consciousness and may cause sudden cardiac death in teenagers and young adults !ho are faced !ith stressors ranging from exercise to loud sounds =CT1 is usually inherited as an autosomal dominant trait 9n the case of =CT'" !hich has been isolated to chromosome ''" mutations lead to serious structural defects in the personFs cardiac potassium channels that do not allo! proper transmission of the electrical impulses throughout the heart There also appear to be other genes" tentatively located on chromosomes #" 0 and '' !hose mutated products may contribute to" or cause" =CT syndrome :eta bloc)ers are used to treat the symptoms of the disease" and appear to be effective in approximately /&''&%&&7'#&f symptomatic patients Ho!ever" common sense therapies such as avoiding strenuous physical exercise and other stressors are also effective +esearch on ho! the genes discussed above interact !ith each other should encourage the development of ne! treatments for =ong5CT syndrome 'ortion of an 5?G used to dia3nose lon3"7T s#ndrome1 an inherited cardiac arr#thmia associated with mutations in an ion channel protein

hromosome **

!7T* Portion of an 3DG used to diagnose long5CT syndrome" an inherited cardiac arrythmia associated !ith mutations in an ion channel protein IMAGE CREDIT: .o%n T. Co&,er%a', Geor(etown )ni$ersit! Medi&al Center, Was%in(ton DC, )SA.

#%

H)AS Three5dimensional structure of +as" the product of an oncogene that is mutated in many human cancers IMAGE CREDIT: Mar, -o(#s,i, NC-I, NIH, -et%esda, MD, )SA

ATM Ataxia5telangiectasia is multi5system disease characteri(ed by cerebellar degeneration" immunodeficiency and predisposition to cancer

D?%4 " Mali3nant Melanoma 3ach year" more than #7"&&& people in the J 1
learn that they have Gmalignant melanoma G G<alignantG means cancerous" and malignant melanoma is a type of cancer that begins in the melanocytes" the cells that form and contain a substance called Gmelanin G ,<elanin is the pigment of the s)in and the amount of it accounts for variations in s)in color in different people and different races <elanocytes are spread throughout the lo!er part of the epidermis" the s)inFs outer layer 2lusters of them are called moles <oles are very commonK most people have bet!een '& and ?& of these bro!n" tan or blac) areas on the s)in They can be raised or flat <oles generally gro! or change only slightly over a long period of time 8ften" the first sign of a melanoma is a change in the si(e" shape or color of an existing mole 9t also may appear as a ne!" abnormal or Gugly5loo)ingG mole <alignant melanoma appears most often in the s)in but may also invade and destroy nearby #0

tissue" 2ancer cells can also spread through the lymphatic system or the bloodstream to other parts of the body and form ne! tumors <elanoma may involve the oral cavity" esophagus" anal canal" vagina" leptomeninges ,delicate membranes surrounding the brain and spinal column-" conjunctivae ,delicate membranes lining the eyelid- and eye 9tFs important that melanoma be detected as early as possible Doctors should chec) their patientsF s)in during routine physical exams and people should also regularly chec) their o!n s)in for ne! gro!ths or other changes 2hanges in the s)in or a mole found during a self5 exam should be reported to the doctor !ithout delay People !ho have had melanoma have a high ris) of developing a ne! melanoma Also" those !ho have relatives !ho have had this disease have a higher5than5average ris) 9t is especially important for these people to chec) their s)in regularly and to have frequent medical exams 9f the doctor suspects that a spot on the s)in is melanoma" the patient !ill need to have a biopsy 9f melanoma is found" the doctor !ill determine the extent or GstageG of disease and then plan appropriate treatment Treatment methods include surgery to remove ,excise- the melanoma ,if the melanoma appears thin and isolated-" and chemotherapy" biological therapy" radiation therapy" or a combination of these methods ,if the cancer has spread-

hromosome 9

D?%4 <alignant melanoma is associated !ith mutation of a tumor suppressor gene involved in cell cycle control IMAGE CREDIT: National Can&er Instit#te

TS * <icroscopic section of #@

angiomyolipoma" a benign tumor of the )idney present in many patients !ith tuberous sclerosis

F.%* " Marfan S#ndrome <arfan syndrome is a connective tissue disorder" so affects many structures" including the
s)eleton" lungs" eyes" heart and blood vessels The disease is characteri(ed by unusually long limbs" and is believed to have affected Abraham =incoln <arfan syndrome is an autosomal dominant disorder that has been lin)ed to the 6:N' gene on chromosome '% 6:N' encodes a protein called fibrillin" !hich is essential for the formation of elastic fibres found in connective tissue *ithout the structural support provided by fibrillin" many tissues are !ea)ened" !hich can have severe consequences" for example" ruptures in the !alls of major arteries :eta bloc)ers have been used to control some of the cardiovascular symptoms of <arfan syndromeK ho!ever" they are not effective against the s)eletal and ocular problems" !hich can also be serious A related disease has been found in mice" and it is hoped that the study of mouse fibrillin synthesis and secretion" and connnective tissue formation" !ill further our understanding <arfan syndrome in humans

hromosome *8

F.%* 3xtracellular fibrillin5' microfibrils ,stained green- are stri)ingly absent in <arfan syndrome ,A- compared to a control sample ,

AT'(A " Menkes' Disease

#A

<en)esF disease is an inborn error of metabolism that mar)edly decreases the cellsF ability to
absorb copper The disorder causes severe cerebral degeneration and arterial changes" resulting in death in infancy The disease can often be diagnosed by loo)ing at a victimFs hair" !hich appears to be both !hitish and )in)ed !hen vie!ed under a microscope <en)esF disease is transmitted as an >5lin)ed recessive trait 1ufferers can not transport copper" !hich is needed by en(ymes involved in ma)ing bone" nerve and other structures A number of other diseases" including type 9> 3hlers5Danlos syndrome" may be the result of allelic mutations ,i e mutations in the same gene" but having slightly different symptoms- and it is hoped that research into these diseases may prove useful in fighting <en)esF disease 9f administered !ithin the first fe! months of life" copper histidinate appears to be effective in increasing the life expectancy of some patients Ho!ever" this treatment only increases life expectancy from three to thirteen years of age" so can only be considered a palliative A similar condition to <en)esF disease exists in miceK !or)ing !ith these model organisms !ill help give insight into human copper transport mechanisms" so helping to develop effective treatments for <en)esF sufferers Abnormal 'urkinEe cell dendrites in the brain of a patient with Menkes disease

hromosome &

DMD Defects in the dystrophin gene cause Duchenne muscular dystrophy" a fatal progressive degeneration of muscle tissue

#/

IMAGE CREDIT: R. Worton, Ottawa General Hospital, Ottawa, CANADA. Adapted for SCIENCE ! ". S#tliff.

AT'(A Abnormal Pur)inje cell dendrites in the brain of a patient !ith <en)es disease

M5%4A " Multiple endocrine neoplasia

<ultiple endocrine neoplasia ,<3N- is a group of rare diseases caused by genetic defects that lead to hyperplasia ,abnormal multiplication or increase in the number of normal cells in normal arrangement in a tissue- and hyperfunction ,excessive functioning- of 7 or more components of the endocrine system 3ndocrine glands are different from other organs in the body because they release hormones into the bloodstream Hormones are po!erful chemicals that travel through the blood" controlling and instructing the functions of various organs Normally" the hormones released by endocrine glands are carefully balanced to met the bodyFs needs *hen a person has <3N" specific endocrine glands" such as the parathyroid glands" the pancreas gland and the pituitary gland" tend to become overactive *hen these glands go into overdrive" the result can beH excessive calcium in the bloodstream ,resulting in )idney stones or )idney damage-K fatigueK !ea)nessK muscle or bone painK constipationK indigestionK and thinning of bones

?&

All forms are transmitted as autosomal dominant traits Type 7A" caused by defect in the <3N7A gene" is characteri(ed by tumors in the pituitary" thyroid" parathyroid and adrenal glands

hromosome *>

M5%4A The syndrome of multiple endocrine neoplasia ,type 7A- is characteri(ed by tumors in the thyroid" parathyroid and adrenal glands IMAGE CREDIT: ". S#tliff, SCIENCE.

$AT The retina of a patient !ith gyrate atrophy of the choroid and retina of the eye caused by ornithine aminotransferase deficiency

MD " M#otonic D#stroph# <yotonic dystrophy is an inherited disorder that primarily affects the muscles" nerves and
digestive tract 1ymptoms of the disease often appear in people in their t!enties" but there is a great deal of variation in its severity and age of onset The disease is caused by an expanding trinucleotide repeat in the D< gene on chromosome '/ This means that each ne! generation has more and more repeats of the trinucleotide in their D< gene This expansion can usually be traced through the female line" and results in a ?'

longer and longer string of the repeat The longer the string" the more severe the symptomsH unaffected people have bet!een % and 7@ copies" mild sufferers have at least %& repeats" !hile more severe cases can have up to a thousand or more <ice can be used as a model organsim for the study of this disease" since they have a similar syndrome Through studying ho! it affects them !e can learn ho! expanding trinucleotide repeats develop" and ho! they might be controlled HuntingtonFs disease is caused by a similar trinucleotide repeat" so any insight into myotonic dystrophy might also provide clues for the treatment of HuntingdonFs and other similar diseas

hromosome *9

A'$5 Atherosclerotic coronary artery disease is associated !ith the gene encoding apolipoprotein 3" a ligand for the =D= receptor IMAGE CREDIT: Mar, -o(#s,i, NC-I, NIH, -et%esda, MD, )SA.

DM <yotonic dystrophy is a muscular disease associated !ith an unstable nucleotide repeat that is amplified bet!een generations

%F4 " %eurofibromatosis1 t#pe 4

Neurofibromatosis" type 7 ,N657- is a rare inherited disorder characteri(ed by the development of benign tumors on both auditory nerves ,acoustic neuromas- 8ther tumors of the central nervous system may also develop ,e g " neurofibromas" meningiomas" gliomas andIor sch!annomas The latter are neoplasms originating in the 1ch!ann cells of the myelin

?7

sheath of neurons - 1ymptoms of N657 may include balance problems" ringing in the ears ,tinnitis- andIor hearing loss N657 is an autosomal dominant genetic trait" meaning it affects both genders equally and that each child of an affected parent has a %&$ chance of inheriting the gene

hromosome 44

DGS Deletion of genes in DiGeorge syndrome is visuali(ed by a fluorescent signal on only one of the t!o copies of chromosome 77 IMAGE CREDIT: Da$id Ian Wilson, )ni$ersit! of New&astle #pon T!ne, )"

%F4 <icroscopic section of a sch!annoma" a tumor commonly found in patients !ith neurofibromatosis" type 7

$.S " $besit# 8besity is an excess of body fat frequently resulting in a significant impairment of health
Doctors generally agree that men !ith more than 7%$ body fat and !omen !ith more than #& &x& &&&&&&&%'%@ap5'&77re obese 8ne can be over!eight !ithout being obeseH a body builder !ho has a lot of muscle" for example 6or practical purposes" ho!ever" most people !ho are over!eight are also obese <any Americans55an estimated ' in ? adults55are at increased health ris) because they are obese" 8besity is a )no!n ris) factor for chronic diseases including heart disease" diabetes" high blood pressure" stro)e and some forms of cancer 9t can also contribute to gallbladder ?#

disease and gallstones" osteoarthritis" gout and pulmonary ,breathing- problems such as sleep apnea" in !hich a person can stop breathing for a short time during sleep 9n scientific terms" obesity occurs !hen a personFs calorie inta)e exceeds the amount of energy he or she burns *hat causes this imbalance is still under investigation 3vidence suggests that obesity has more than one cause Genetic" environmental" psychological and other factors all may play a part The obese ,8b- mutation that has been found in the mouse provides a useful model for studying human obesity 8besity tends to run in families" suggesting that it probably has a genetic cause in humans Ho!ever" family members share not only genes but also diet and lifestyle habits that may contribute to obesity 1eparating these lifestyle factors from genetic ones is often challenging 1till" gro!ing evidence points to heredity as a strong determining factor of obesity 9n one study of adults !ho !ere adopted as children" researchers found that the subjectsF adult !eights !ere closer to their biological parentsF !eights than their adoptive parentsF The environment provided by their adoptive family apparently had less influence on the development of obesity than the personFs genetic ma)eup People canFt change their genetic ma)eup but they can change !hat they eat and their level of activity 1ome people have been able to lose !eight and )eep it off byH learning ho! to choose more nutritious meals that are lo!er in fatK learning to recogni(e environmental cues ,such as enticing smells- that may ma)e them !ant to eat !hen they arenFt hungryK and becoming more physically active 1ome individuals have had great success using behavior modification techniques to control obesity 9n some cases of severe obesity" gastronintestinal surgery may be recommended

hromosome (

FT) The gene encoding a chloride ion channel is defective in patients !ith cystic fibrosis IMAGE CREDIT: 0. Alaw1ati, Col#' ia )ni$ersit!, N2, )SA. Adapted ! ". S#tliff, SCIENCE.

??

$.S The obese ,8b- mutation in the mouse provides a useful model system for studying human obes

'AH " 'hen#lketonuria /'?C0 Phenyl)etonuria ,PDJ- is a rare metabolic disorder of infancy caused by a deficiency of the
liver en(yme phenylalanine hydroxylase PDJ prevents the affected individual from normally metaboli(ing phenylalanine ,phe-" one of the essential amino acids found in all protein foods Phenyl)etonuria is a severe progressive disorder that can produce mental retardation if it is not treated early 8ther manifestations such as s)in rash" sei(ures" excessive restlessness" irritable behavior and a musty body odor may also be present 6ortunately" detection of the condition shortly after birth through the use of a routine blood screening procedure has become standard practice in every state since '//' Placing the baby on a phenylalanine5restricted diet !ithin the first !ee)s of life" and maintaining good diet control thereafter" is effective in preventing the damaging effects of PDJ Treatment requires elimination of foods naturally high in protein 1pecial care must be ta)en to maintain enough" but not too much" phe in the childFs diet 1uch a balance is obtained only through careful nutritional" biochemical and medical supervision" and considerable effort by the parents

hromosome *4
?%

'&)* Peroxisomes are not detected in Eell!eger syndrome fibroblasts ,A- but can be reconstituted by transfection !ith P>+' gene ,:IMAGE CREDIT: Nan&! -ra$er'an, Ga rielle Dodt, H#(o Moser, Step%en Go#ld and Da$id /alle fro' t%e .o%ns Hop,ins )ni$ersit!, -alti'ore, MD, )SA.

'AH <illions of ne!borns per year are screened for deficiency of phenylalanine hydroxylase to identify those susceptible to phenyl)etonuria ,PDJ-

'?D* " 'ol#c#stic ?idne# Disease

Adult polycystic ,Gcontaining or made up of many cystsG- )idney disease is characteri(ed by large cysts in one or both )idneysK patients eventually die from renal failure or consequences of hypertension ,high arterial blood pressureThe t!o )idneys in the human body are located in the lumbar region They filter the blood" excreting the end5products of body metabolism in the form of urine and regulating the concentrations of hydrogen" sodium" potassium" phosphate and other ions in the extrcellular fluid

hromosome *D

?0

'?D* Adult polycystic )idney disease is characteri(ed by large cystsK patients eventually die from renal failure or consequences of hypertensi

).* " )etinoblastoma

2hildhood tumors of the retina are associated !ith inactivation of the retinoblastoma gene +etinoblastoma is the commonest malignant eye tumor of childhood" occurring in about ' in 7&"&&& live births The disorder is due to tumor cells appearing in one or both eyes in children under % years of age 9t is usually diagnosed initially by a bright !hite or yello! mass in the pupillary area" behind the lens +etinoblastoma is seen in a hereditary and non5hereditary form 9n hereditary retinoblastoma" there is a germ cell mutation !hich predisposes the individual to the development of the retinal tumor Jntreated" retinoblastoma is almost uniformly fatal" but !ith modern methods of treatment the survival rate is over /&$

hromosome *+

.) A4 <ammogram sho!ing breast cancer IMAGE CREDIT: +at Connell!, Mia'i /alle!

?@

Hospital, Da!ton, OH, )SA

).* 2hildhood tumors of the retina are associated !ith inactivation of the retinoblastoma gene IMAGE CREDIT: ".S#tliff, SCIENCE

AT'(. 9n *ilsonFs disease" toxic levels of copper accumulate and damage many tissues and organs" including the basal ganglia of the brain

ADA " Se;ere ombined @mmunodeficienc#

G9mmunodeficiencyG refers to a substandard immune response or a disorder characteri(ed by deficient immune response 1evere combined immunodeficiency ,129D- is the term for a group of rare genetic disorders charateri(ed by gross impairment of the immune system" manifested by lac) of formation of antibodies to !ard off infection and other challenges 6or a person !ith this condition" blood transfusions can result in graft5versus5host ,GBH- disease and routine vaccinations may bring fatal infection Jnless immune function is restored by a bone marro! or fetal tissue transplant" or the patient is )ept in isolation" death from opportunistic infection usually occurs before the first birthday

hromosome 4>

?A

ADA Gene therapy has been attempted to treat severe combined immunodeficiency caused by a missing en(yme" adenosine deamina

S ! * " !un3 ancer

9n the J 1 " lung cancer is the most common cause of cancer deaths among both men and
!omen 9n fact" north Americans have the highest rates of lung cancer in the !orld :y the end of '//0" some '@@"&&& ne! cases !ill have been diagnosed and roughly '%A"@&& deaths from the disease !ill have occurred 1adly" the %5year survival rate for persons !ith lung cancer is only '#$ & 1ince the '/?&s" the increase in lung cancer mortality by gender has follo!ed historic patterns of smo)ing" !ith a 7&5year time lag About /&@7%&&&'#&?f male lung cancer deaths and A&@7%&&&'?'#f female lung cancer deaths are attributable to cigarette smo)ing Ho!ever" smo)ing cessation reduces the ris) of lung cancer mortality at any age Although smo)ing is by far the major cause of lung cancer" it is not the only cause 3xposure to other peopleFs tobacco smo)e ,Genvironmental tobacco smo)eG or Gsecond5hand smo)eGincreases the ris) of lung cancer among nonsmo)ers 3xposure to certain carcinogens" such as asbestos" in the !or)place also increases ris) of lung cancer And !or)ers ,especially smo)ers- !ho are exposed to high levels of radon" a radioactive gas" have an increased rate of developing lung cancer ,+adon levels in homes are generally much lo!er and researchers are trying to determine !hether exposure to radon at home can increase lung cancer ris) =ung cancer usually does not cause symptoms !hen it first develops 9n time" though" the gro!ing tumor causes symptoms to appear These can include a persistent cough" constant chest pain" shortness of breath" !hee(ing" repeated bouts of pneumonia or bronchitis" coughing up blood" and hoarseness =i)e all cancers" lung cancer can cause fatigue" loss of appetite" and !eight loss =ung cancer often spreads to lymph nodes or other tissues in the chest ,including the other lung- 9n many cases" lung cancer also spreads to other parts of the body" such as the bones" brain or liver 9f the cancer spreads to other areas" it may cause headache" pain" or bone fractures Treatment of lung cancer depends on many factors" including type of lung cancer" si(e and

?/

location of the tumor" and stage of the disease 1urgery" radiation therapy and chemotherapy are the usual treatments

hromosome +

=H! <icroscopic section of hemangioblastoma" a tumor of the cerebellum characteri(tically found in patients !ith von Hippel5 =indau disease IMAGE CREDIT: "e$in Rot% and Ro ert S&%'idt, Was%in(ton )ni$ersit!, St. *o#is, MO, )SA

S ! * Deletion of a tumor suppressor gene is associated !ith one type of lung cancer A large tumor ,2a- of the lung is visible in this 2T scan IMAGE CREDIT: +at Connell!, Mia'i /alle! Hospital, Da!ton, OH, )SA

%&

M!H* 6or this gene" as for <1H7" homologies to genes in DNA repair path!ays in model organisms such as yeast shed light on human patholog

S A* " Spinocerebellar Atroph# Persons !ith spinocerebellar atrophy experience a degeneration of the spinal cord and the
cerebellum" the small fissured mass at the base of the brain" behind the brain stem The cerebellum is concerned !ith coordination of movements" so atrophy or G!asting a!ayG of this critical control center results in a loss of muscle coordination Atrophy in the spine can bring spasticity 1pinocerebellar atrophy is a Ghereditary ataxia"G meaning it is a disorder that causes ataxia ,lac) of coordination- and that it runs in families 1ymptoms include clumsiness" poor coordination of all voluntary movement ,but chiefly the eyes" arms" hands and legs- and difficulty !ith speech 6atigue and irregular blood pressure may also affect the patient !ith spinocerebellar atrophy The most disabling feature of spinocerebellar atrophy is the loss of balance Persons !ith the disease are frequently !heelchair5bound for this reason" not because of physical !ea)ness 1pinocerebellar atrophy may sho! itself during childhood" youth or adulthood 1uggested diagnostic methods include a magnetic resonance imaging ,<+9- exam" !hich may sho! atrophied areas" and a thorough neurologic exam 6or persons !ith Type 9 or Type 999 of spinocerebellar atrophy" a commercially5 available test offers greater ease of diagnosis

hromosome D

%'

S A* Degeneration of the cerebellum leads to loss of muscle coordination in patients !ith spinocerebellar atrophy IMAGE CREDIT: "e$in Rot% and Ro ert S&%'idt, Was%in(ton )ni$ersit!, St. *o#is, MO, )SA.

@DDM* .uvenile onset diabetes" in !hich the bodyFs o!n T lymphocytes infiltrate and destroy insulin5producing pancreatic islet cells" is associated !ith the major histocompatibility complex

S)D8A* " Steroid 8"alpha reductase

Discovery of the plant homolog of human steroid %5alpha reductase lin)s botany to endocrinology and may lead to ne! drugs The S)D8A* 3ene maps to chromosome 8

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hromosome 8

DTD. )adio3raph of the hand of a patient with diastrophic d#splasia1 caused b# mutations in a 3ene encodin3 a sulfate transport protein @MAG5 )5D@TA 5ric !ander1 <hitehead @nstitute1 M@T1 ambrid3e1 MA1 CSA

S)D8A*. Disco;er# of the plant %#

homolo3 of human steroid 8" alpha reductase links botan# to endocrinolo3# and ma# lead to new

D' - " 'ancreatic cancer

The pancreas is a large" elongated gland situated behind the stomach 9t produces and secretes directly into the bloodstream the hormone insulin" along !ith other substances crucial to the bodyFs operation The pancreas also plays a )ey role in the digestion of protein There !ill be an estimated 70"#&& ne! cases of pancreatic cancer in the J 1 this year" and an expected 7@"A&& deaths from the disease Pancreatic cancer occurs more frequently in blac) Americans than in !hite Americans Bery little is )no!n about cancer of the pancreas" or ho! to prevent it +is) increases after age %&" !ith most cases occurring bet!een ages 0% and @/ 1mo)ing is a ris) factorK incidence rates are more than t!ice as high for smo)ers as for nonsmo)ers 1ome studies have suggested associations !ith other health problemsH chronic pancreatitis" diabetes" or cirrhosis 9n countries !here the diet is high in fat" pancreatic cancer rates are higher 2ancer of the pancreas generally occurs !ithout symptoms until it is in advanced stages and %?

thus is considered a GsilentG disease At present" only surgical biopsy yields a certain diagnosis and" because of the GsilentG course of the disease" the need for biopsy is li)ely to be obvious only after the disease has advanced +esearchers are focusing on !ays to diagnose pancreatic cancer before symptoms occur Jltrasound imaging and computeri(ed tomography scans are under investigation 9n the fight against pancreatic cancer" surgery" radiation therapy and anticancer drugs are treatment options" but have had little influence on the outcome Diagnosis is usually so late that none of these is used 6or all stages of this type of cancer combined" the one5year relative survival rate is only 7&$" and the %5year rate is ?$

hromosome *:

D' - =oss of this gene causes pancreatic cancers to gro! aggressively" as seen by tumor cells invading a nerve bundle

TDF " Testis Determinin3 Factor

The testis is another term for the male gonad ,A gonad is a sex gland in !hich gametes 55 mature sexual reproductive cells 55 are produced - The testis is also called a Gtesticle G The testis can be either of a pair of egg5shaped glands normally situated in the scrotum 8n the 4 chromosome" TD6 or Gtestis5determining factorG binds to DNA and regulates genes controlling the development of the testis Testis"determinin3 factor /also known as S)90 binds to D%A and re3ulates 3enes controllin3 the de;elopment of the testis

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hromosome 9

TDF Testis5 determining factor ,also )no!n as 1+4- binds to DNA and regulates genes controlling the development of the tes

TS " Tuberous Sclerosis

Tuberous sclerosis is a hereditary disorder characteri(ed by benign" tumor5li)e nodules of the brain andIor retinas" s)in lesions" sei(ures andIor mental retardation Patients may experience a fe! or all of the symptoms !ith varying degrees of severity

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hromosome 9

D?%4 <alignant melanoma is associated !ith mutation of a tumor suppressor gene involved in cell cycle control IMAGE CREDIT: National Can&er Instit#te

TS * <icroscopic section of angiomyolipoma" a benign tumor of the )idney present in many patients !ith tuberous sclerosis

T'8+ " Tumor Suppressor T'8+

TP%# is a tumor suppressor gene that" !hen mutated or deleted" can be involved in the development of a !ide variety of tumors 9ellow dots indicate some of the man# t#pes of tumors that carr# mutations in the p8+ 3ene

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hromosome *(

T'8+ 4ello! dots indicate some of the many types of tumors that carry mutations in the p%# gene IMAGE CREDIT: ". S#tliff and C. +a er S'it%. Reprinted fro' SCIENCE.

.) A* Distribution of mutations in the :+2A' gene !ich is associated !ith early5onset breast and ovarian cancer canc

=H! " =on Hippel"!indau Disease

Bon Hippel5=indau ,BH=- disease is an inherited multi5system disorder characteri(ed by abnormal gro!th of blood vessels in certain parts of the body *hile blood vessels normally gro! li)e trees" in people !ith BH= little )nots of blood capillaries sometimes occur These )nots are called angiomas or hemangioblastomas The disease is different in every patient Gro!ths may develop in the retinas" certain areas of the brain" the spinal cord" the adrenal glands and other parts of the body =esions in the retina may cause retinal detachment and eventual blindness 2ataracts and glaucoma may occur as !ell Angiomas in the brain or spinal cord may press on nerve or brain tissue and cause symptoms such as headaches" problems !ith balance in !al)ing" or !ea)ness of arms and legs Ho!ever" symptoms vary greatly and depend on the si(e and location of the gro!ths Bon5Hippel =indau disease is transmitted genetically 9t is caused by a dominant type of gene

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A child receives one gene of each pair from each parent 9f one parent has a dominant gene" each child has a %&5%& chance of inheriting that gene Age of onset varies but is most common in the fourth decade People !ith von Hippel5=indau disease are also predisposed to certain types of malignant tumors" i e" renal cell carcinoma 1creening methods include a thorough eye exam" a physical exam including blood pressure chec) and neurological examination" imaging of the head and an ultrasound of the abdomen *ith careful monitoring" early detection and appropriate treatment" the harmful effects of the defective BH= gene can be greatly reduced" or perhaps even prevented entirely

hromosome +

=H! <icroscopic section of hemangioblastoma" a tumor of the cerebellum characteri(tically found in patients !ith von Hippel5 =indau disease IMAGE CREDIT: "e$in Rot% and Ro ert S&%'idt, Was%in(ton )ni$ersit!, St. *o#is, MO, )SA

S ! * Deletion of a tumor suppressor gene is associated !ith one type of lung cancer A large tumor ,2a- of the lung is visible in this 2T scan IMAGE CREDIT: +at %/

Connell!, Mia'i /alle! Hospital, Da!ton, OH, )SA

M!H* 6or this gene" as for <1H7" homologies to genes in DNA repair path!ays in model organisms such as yeast shed light on human pathol

'A&+ " <aardenbur3 S#ndrome *aardenburg syndrome ,*1- is a genetic disorder the main characteristics of !hich
includeH a !ide bridge of the noseK pigmentary disturbances such as t!o different colored eyes ,generally one is bro!n and the other bright blue" although occasionally patches of bro!n and blue are mixed in the same eye-"!hite foreloc) ,loc) of hair gro!ing from the front part of the head-" !hite eyelashes and premature graying of the hairK and some degree of cochlear deafness 9n addition to these three primary features" there may also be cleft lip andIor cleft palate" and enlargement of the colon Ho!ever" these are less common than the primary features Type 9 of the disorder is characteri(ed by displacement of the fold of the eyelid" !hile type 99 does not include this feature Ho!ever" the frequency of deafness is higher in type 99 8ther than hearing loss" most people !ith *1 do not have any particular medical problems The facial features and pigmentary changes just help in ma)ing the diagnosis and cannot be considered abnormal :ecause *1 is inherited in dominant fashion" researchers typically see families !ith several generations !ho have inherited one or more of the features <any of these people are una!are that they have the gene because the accompanying symptoms can be so mild The chance of GcarriersG passing on the gene to their children is %&$" regardless of the features they possess 8f course" someone in a *aardenburg syndrome family !ho does not have the gene cannot pass it on *1 may be much more common in our population than previously believed As many as 75# out of every hundred children in schools for the deaf may have *1 1ince the majority of those !ith the gene have little or no hearing loss" experts believe that for every child they see !ith *1 and severe hearing loss" there are ?5% family members !ho have relatively normal

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hearing but also have the gene The discovery of the human gene that causes *1" Gpax#"G came about after scientists speculated that Gsplotch mice"G !hich have splotchy coloring in their coats" might have the same gene that causes *1 in humans They located the gene that causes the irregular coloring in mice" then found the same gene" !hich does cause *1" in humans *ith a mouse model to dra! from" scientists are learning much about ho! pax# causes *aardenburg syndrome

hromosome 4

MSH4 A human gene mutated in some colon cancers is homologous to an en(yme in the DNA mismatch repair path!ay in bacteria

'A&+ Portion of a pedigree of *aardenburg syndrome" indicating the occurrence of deafness and changes in pigmentation" including a !hite foreloc)

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<)% " <erner's S#ndrome

*ernerFs syndrome is a form of premature aging ,progeria- !hich begins in adolescence or early adulthood and results in the appearance of old age by #&5 ?& years of age The disorder is inherited" transmitted as an autosomal recessive trait 9ts physical characteristics may

07

include short stature ,common from childhood on- and other features usually developing during adulthoodH !rin)led s)in" baldness" cataracts" muscular atrophy" and a tendency to diabetes mellitus" among others

hromosome :

<)% *ernerFs syndrome is a disease of premature and accelerated aging associated !ith defects in a DNA un!inding en(yme IMAGE CREDIT: Willia' and Wil,ens +# lis%in( Co.

M9 A reciprocal chromosome translocation involving the c5myc oncogene is associated !ith :ur)itt lymphoma

AT'(. " <ilson's Disease

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*ilsonFs disease is a rare genetic disorder characteri(ed by the accumulation of copper in various body tissues" particularly the liver" brain and corneas The illness is inherited as an autosomal recessive trait and attributable to a defect in the metabolism of copper *ilsonFs disease is characteri(ed by cirrhosis of the liver and degenerative changes in the brain =iver disease is the most common symptom in childrenK neurologic disease is most common in young adults 9n the eye" the characteristic feature is a pigmented ring ,called the Dayser5 6leischer ring- at the outer margin of the cornea 3arly diagnosis and treatment may prevent serious long5term disability

hromosome *+

.) A4 <ammogram sho!ing breast cancer IMAGE CREDIT: +at Connell!, Mia'i /alle! Hospital, Da!ton, OH, )SA

).* 2hildhood tumors of the retina are associated !ith inactivation of the retinoblastoma gene IMAGE CREDIT: ".S#tliff, SCIENCE

AT'(. 9n *ilsonFs disease" toxic levels of copper 0?

accumulate and damage many tissues and organs" including the basal ganglia of the brai

FM)* " Fra3ile & S#ndrome

6ragile > syndrome is the most common genetically5inherited form of mental retardation currently )no!n 9t is a defect of the > chromosome and occurs more frequently and severely among males than females The observable characteristics of 6ragile > occur in approximately ' in '"&&& male births and ' in 7"%&& female births 9n addition to intellectual disability" some individuals !ith 6ragile > display common physical traits and characteristic features" such as prominent ears" a high forehead and a big ja! 2hildren !ith 6ragile > often appear normal in infancy but develop typical physical characteristics during their lifetime <ental impairment may range from mild learning disability and hyperactivity to severe mental retardation and autism Also among the !ide range of symptoms associated !ith the disorder areH language delaysK behavioral problemsK the poor eye contact and hand5flapping that accompany autism or autistic5li)e behaviorK enlarged external genitalia ,macroorchidism-K and poor sensory s)ills 9n normal individuals the 6<+' gene is passed on" in stable fashion" from the parent to the offspring 9n 6ragile > individuals" the repeated sequences not only expand abnormally but are unstable and the degree of impairment in offspring may vary The 6ragile > mutation appears to increase in length as it is inherited by succeeding generations" a phenomenon )no!n as Ggenetic anticipation G

hromosome &

DMD Defects in the dystrophin gene cause Duchenne muscular dystrophy" a fatal progressive degeneration of muscle tissue IMAGE CREDIT: R. Worton, Ottawa General Hospital, Ottawa, CANADA. Adapted for SCIENCE ! ". S#tliff.

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AT'(A Abnormal Pur)inje cell dendrites in the brain of a patient !ith <en)es disease IMAGE CREDIT: "e$in Rot% and Ro ert S&%'idt, Was%in(ton )ni$ersit!, St. *o#is, MO, )SA

FM)* An unstable nucleotide repeat is associated !ith the most common form of mental retardation )no!n as 6ragile > syndrome IMAGE CREDIT: Ste$e Warren, E'or! )ni$ersit! S&%ool of Medi&ine, Atlanta, GA, )SA.

A!D <ylein5stained section of brain in adrenoleu)odystrophy" characteri(ed by defective catabolism of long chain fatty acid 00

'&)* " Fellwe3er S#ndrome

Eell!eger syndrome is a rare hereditary disorder affecting infants The disease is characteri(ed by reduction or absence of peroxisomes 55 microbodies in vertebrate animal cells" especially liver" )idney and brain cells" !hich are rich in several en(ymes Jnusual problems in prenatal development" an enlarged liver" high levels of iron and copper in the blood" and vision disturbances are among the major manifestations of Eell!eger syndrome 'ero6isomes are not detected in Fellwe3er s#ndrome fibroblasts /A0 but can be reconstituted b# transfection with '&)* 3ene /.0

hromosome *4

'&)* Peroxisomes are not detected in Eell!eger syndrome fibroblasts ,A- but can be reconstituted by transfection !ith P>+' gene ,:IMAGE CREDIT: Nan&! -ra$er'an, Ga rielle Dodt, H#(o Moser, Step%en Go#ld and Da$id /alle fro' t%e .o%ns Hop,ins )ni$ersit!, -alti'ore, MD, )SA.

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'AH <illions of ne!borns per year are screened for deficiency of phenylalanine hydroxylase to identify those susceptible to phenyl)etonuria ,PDJ-

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