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.................................................................................... 9
......................................................................................................... 13
......................................................................................................... 15
ABSTRACT .......................................................................................................... 17
............................................................................................. 19

1. ....................................................................................................... 21
1.1 .......................................................................................................... 21
1.2 ............................................................................................... 25
1.3 ......................................................................................... 26
1.3.1 3 ..................................................... 26
1.3.2 ......................................................................... 27
1.3.3 ........................................................ 29
1.3.4 ......................................... 30
1.3.5 , ............. 32
1.3.6 ........................................................ 33
1.3.7 ............................................. 34
1.4 ...................................................................................................... 34
1.4.1 ............................................................................................. 36
1.4.2 .............................................................................. 37
1.4.3 ........................................................................ 38
1.4.4 ................................................................................ 39
1.5 ............................................................................................... 40
1.5.1 ......................................... 40
1.5.2 .......................................... 43
1.5.3 ............................................................................. 44
1.5.4 .......................... 45
1.6 ......................................................................................... 47
1.6.1 ....................................................................................... 48
1.6.2 .................................................................................... 49
1.6.3 ...................................................................... 52
1.6.3.1 ................. 52
6
. SHANK3 (22q13.3) ................................................................................... 53
II. : NLGN3 (Xq13.1) & NLGN4X (Xp22.33) ................................ 55
II. : NRX1 (2p16.3), NRX2 (11q13) & NRX3 (14q31).............. 66
IV. CNTN4 (3p26.3) & CNTN3 (3p12.3) ........................................................ 67
V. CNTNAP2 (7q35) ..................................................................................... 68
1.6.3.2 ................................................................... 70
. RELN (7q22) ............................................................................................ 70
I. 2 (7q36) ............................................................................................ 70
1.6.3.3 ...................................... 72
. OXTR (3p25) ........................................................................................... 72
I. GRIK2/GluR6 (6q21) ............................................................................... 73
II. SLC6A4 (17q11.1-12) ............................................................................ 73
V. ITGB3 (17q21.32) .................................................................................. 73
1.6.3.4 ....................................................................................... 74
. SLC25A12 (2q24) ..................................................................................... 74
I. (7q31.2) ......................................................................................... 75
II. PTEN (10q23.3) .................................................................................... 76
1.6.4 (CNVs) ..................................................... 77

2. .................................................................................. 80
3. ..................................................................................... 81
3.1 ............................................................................................................... 81
3.1.1 ........................................................................................ 81
3.2 .......................................................................................................... 87
3.2.1 , ............................................................... 87
3.2.2 DNA ......................................................................................... 88
3.2.3 ........................................ 91
3.2.4 PCR ................................. 95
3.2.5 DNA.................................................................. 96
3.2.6 ARMS PCR ......................................... 98
3.2.6.1 ARMS PCR c.222C>T (p.Y74Y)100
3.2.6.2 ARMS PCR c.-705A>G ............................. 102
3.2.6.3 ARMS PCR c.-206G>C ............................. 103
7
3.2.6.4 ARMS PCR c.1597A>G (p.K378R)............. 104
3.2.7
(dHPLC) ...................................................... 105
3.2.7.1 dHPLC 6 NLGN3 5
NLGN4X ........................................................................................... 107
3.2.8 DNA ................................................ 110
3.2.9 sequencing MegaBACE .................................................... 112
3.2.9.1 DNA ................................ 113
3.2.9.2 PCR sequencing
NLGN3 NLGN4X .......................................................................... 114
3.2.9.3 PCR ................................................................ 118
3.2.9.4 sequencing ........................................................................ 119
3.2.9.5 sequencing ............................ 119
3.2.10 .................................................... 121
4. ........................................................................................... 122
4.1 ARMS PCR c.222C>T (p.Y74Y)
(NLGN3, 2).................................................................................................. 122
4.2 dHPLC NLGN3,
6 .......................................................................................................................... 123
4.3 dHPLC NLGN4,
5 .......................................................................................................................... 125
4.4 NLGN3
NLGN4X ................................................................................................................ 129
5. .................................................................................................... 139
6. ............................................................................................ 154

: .
: 16 1980
: 7, ,
: 210 9953728 / 6932322103
E-mail: tina.volaki@gmail.com
8.2005 4.2012:
, , -

:
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9.1998 - 6.2002: BSc in Biological Sciences with Honours in Genetics

, .
: Second Class Honours (Second Division)
1998: International Baccalaureate, -

, . : 40 / 45
9.2009 7.2011: International

Baccalaureate. -
11.2004 - 6.2005: .
DEMO BE
9
6.2001- 7.2001: Screening with 53BP1 to isolate a protein
partner which recruits 53BP1 to the sites of DNA damage after ionising irradiation
Dr. Yasuhisa Adachi, ,

1. Volaki Konstantina, Pampanos A, Kitsiou-Tzeli S, Vrettou C, Oikonomakis V,

Sofocleous C, Mavrou A, Kanavakis E. Mutation screening in Greek population and
evaluation of NLGN3 and NLGN4X genes as a causal factor for autism. Psychiatric
Genetics [under peer review].
2. Pampanos A, Volaki Konstantina, Kanavakis E, Papandreou O, Youroukos S,

Thomaidis L, Karkelis S, Tzetis M, Kitsiou-Tzeli S. A substitution involving the NLGN4
gene associated with autistic behavior in the Greek population. Genetic Testing and
Molecular Biomarkers. 2009 Oct;13(5):611-5.
3. , , , - .
: . 2006; 69 (5): 327-335.
1. Volaki K, Pampanos A, Kanavakis E, Oikonomakis V, Vrettou C, Papadaki-

Papandreou O, Giouroukos S, Thomaidou L, Tzetis M, Kitsiou-Tzeli S. Mutation
analysis of NLGN3 and NLGN4 genes in Greek autistic patients. XVIII World
congress on Psychiatric Genetics: Genes to biology. Athens, Greece 2010.
2. , , ., - .,
., ., ., - .
10
.
: ,
. ...../ ... . , 2009.
3. Volaki K, Pampanos A, Papadaki-Papandreou O, Thomaidou L, Giouroukos S,

Oikonomakis V, Kanavakis E, Kitsiou-Tzeli S. Poster presentation: substitution
mutation of NLGN4 in the Greek autistic population. XX International congress of
genetics: Understanding living systems. Berlin, Germany, 2008.
4. Volaki K, Pampanos A, Papadaki-Papandreou O, Giouroukos S, Thomaidou L,

Oikonomakis V, Kanavakis E, Kitsiou-Tzeli S. ncidence of NLGN genes in Greek autistic
patients. European uman Genetics Conference. Barcelona, Spain, 2008.
5. Pampanos A, Volaki K, Papadaki-Papandreou O, Thomaidou L, Giouroukos S,

Kanavakis E, Kitsiou-Tzeli S. Neuroligin (NLGN3/NLGN4) contribution regarding autistic
behavior. 21o :
. , 2007.
6. Pampanos A, Volaki K, Thomaidou L, Giouroukos S, Papadaki-Papandreou O, Kitsiou-

Tzeli S, Kanavakis E. Molecular analysis of patients with autistic behaviour. 3rd
International congress on brain and behaviour and 16th Thessaloniki conference of the
south-east European society for neurology and psychiatry 2007.
7. , , , , - ,
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(NLGN3/NLGN4) .
: , . ....., , 2007.
8. , , - , , ,
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2007.
11

2001 2012:
: Proficiency Cambridge
: Certificat Pratique de Langue Franaise (1er Degr), Universit de Paris

Sorbonne
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14

. 3 ,
. , ,
, NLGN3 (Xq13.1)
NLGN4X (Xp22.33), ,
, 169
() : 1) o o 6 NLGN3 o o 5 NLGN4X, 2)
c.222C>T (p.Y74Y) 2 NLGN3. ,
40 169 ,
DNA NLGN3 NLGN4X.
NLGN4X : ) , c.1597A>G
5, p.K378R, )
, c.-206G>C 5 ( 2), )
SNP, rs111953947, c.-705A>G, .
15
,
NLGN3 NLGN4 ,
() .
, .
16
ABSTRACT
Autism belongs to the category of neurodevelopmental disorders and is
characterized by difficulties in social interaction and communication as well as
stereotypical types of behaviour. The first signs of the disorder have an onset at the age
of 3 but its development is variable with respect to severity and clinical heterogeneity.
The aetiology of autism has not yet been elucidated. Many factors are involved, including
genetic, neuroanatomic, environmental and various pathological conditions, which interact
and contribute in different ways and degrees to the onset and development of the
disorder. During the last decade, predisposing genes and genetic loci are under
investigation.
Mutations in two X-linked neuroligin genes, NLGN3 (Xq13.1) and NLGN4X
(Xp22.33), have been implicated in the pathogenesis of autism. The present study aims to
explore for the first time the contribution of NLGN3 and NLGN4X genetic variants in Greek
patients with Autism Spectrum Disorders (ASD), in order to investigate further the
potential contribution of mutations in these two genes in individuals with this disorder.
Based on published literature, 169 patients with ASD were screened for: 1) mutations in
exon 6 of NLGN3 and exon 5 of NLGN4X, and 2) the presence of mutation c.222C>T
(p.Y74Y) in exon 2 of NLGN3. In addition, 40 patients with diagnosis of autistic disorder
were selected out of 169 and sequenced on the full length coding regions of the NLGN3
and NLGN4X genes. Interesting nucleotide changes were identified in NLGN4X : a) one
substitution mutation, c.1597A>G in exon 5, leading to the amino acid substitution
p.K378R in the protein, b) one novel variant, c.-206G>C, in the 5 untranslated region of
exon 2, c) one non-validated SNP, rs111953947, in the promoter. Analysis performed
predicts that the above variants are benign or polymorphisms.
17
The low frequency of mutations in NLGN3 and NLGN4X genes reported in the
literature, in addition to the lack of association of mutations with specific phenotypes, do
not encourage the wide application of clinical screening of these two genes in patients
with ASD. Overall, it seems that one variation in one neuroligin gene cannot sufficiently
account for ASD and cognitive underdevelopment in the majority of cases. Development
of the ASD phenotype emanates from interacting gene variants in various cellular
pathways under the influence of epigenetic and/or environmental factors. Assessment and
evaluation of genetic findings in ASD needs comprehensive data management with large-
scale research, in order to unveil eventually a more lucid picture on the pathogenesis of
ASD.
18

ADI-R Autism Diagnostic Interview- Revised
ADOS-G Autism Diagnostic Observation Schedule-Generic
AGP Autism Genome Project
AGRE Autism Genetic Resource Exchange
ARMS PCR Amplification refractory mutation system PCR
ASD Autism Spectrum Disorders
ASP affected sib pairs
bp base pair
CNVs Copy Number Variations -
dHPLC denaturing High Performance Liquid Chromatography
dNTP Deoxyribonucleotide triphosphate
DSM Diagnostic and Statistical Manual of Mental Disorders

fMRI Functional magnetic resonance imaging -

GWAS Genome-wide association studies

ICD International Classification of Diseases

NLGN Neuroligin -
NRXN Neurexin -
PCR Polymerase chain reaction
PSD-95 Post-synaptic density protein 95
SNP Single nucleotide polymorphism
WGA Whole Genome Amplification
19
- -
20

1.
1.1
E Bleuler 1911
,
[1]
. Leo Kanner 1943,
11 ,
. o

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A Hans Asperger 4 ,
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Kanner .
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[18]
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. 1980,
Kanner Rutter ,
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25
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Developmental Disabilities Monitoring Network) 57% o

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27
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Wing L. Gould J. (1979)
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3-7%.
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4.0%

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2: ( :
Turner M, et al. Molecular Medicine Today 2000 (vol. 6).
1.4.2
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[62]
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[69-71] [72-74]
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41

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(fMRI),
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fMRI
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42
1.5.2
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(pars opercularis)
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association studies - GWAS) , (Linkage studies),
(Copy Number Variants CNVs).
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), .

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48
2q21
[113-118]
33, 3q2527, 3p25, 4q32, 6q1421, 7q22, 7q3136, 11p1213, 17q1121 .
- 7q22-32
[119]
10p12-q11.1 17p11.2-q12 .
- Autism
[118]
Genome Project (AGP) Consortium 1181 multiplex .

[120]
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[121-125]
2q 7q35 .
[126]
19p13 ,
[127]
7q 21q ,
[128]
1q . ,
[129]
15q1113 .
1.6.2
49
[112]
.
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. 100
. 1.6.3
(GWAS)
, ,
,
[130]
.
GWAS .
780 (3101 ) 1204
6 SNPs (Single nucleotide polymorphisms)
5p14.1,
9 10 (CDH9, CDH10).
, CDH10 ,
[131]
.
50
SNP Semaphorin 5A 1031 .
5p15 .
,
[132]
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1558
MACROD2, [133].
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Wang et al.
AGP
[134]
Consortium .
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CDH8,
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(purifying selection).

[136]
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51
.
: 1) , 2)
, 3)
4)
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.
1.6.3
1.6.3.1
, PSD-95 (post-
synaptic density protein 95),
( 3).
PSD-95 -
, ,
[137-139]
.
, SHANK3,
52
3:
(, )
(, , CNTNAP2, ) ,
.
(PSD-95, SHANK), (, , )
(CASK, MAPK), , ,
[140]
.
. SHANK3 (22q13.3)
SHANK3 PSD-95
[141, 142] [143] [144]
. SHANK3
.
[145]
.
, SHANK3
53
[146]
. SHANK3
[147]
.
22q13.3,
SHANK3, , ,
, ,
[148-153]
. ,
SHANK3
SHANK3 .
300 , 3 : 1) de novo
142bp 8 (proband) , 2)
Asperger 3)
22q13 22q13 Asperger

[154]
, . de novo
22q13 , 400 .

[155]
. de novo
(donor splice site)
2 427
[156]
.
, CNVs SHANK3
[157]
.
SHANK3 0.5-1%.
54
.
SHANK3 ,
. ,
PSD-95, ,
-).
SHANK3
[158]
.
. : NLGN3 (Xq13.1) & NLGN4X (Xp22.33)
: NLGN1 ( 3,
3q23.32, 885Kb, 7 ), NLGN2 ( 17, 17p13.2,
106Kb, 23 ), NLGN3 ( , q13.1, 32Kb, 8 ),
NLGN4X ( , p22.33, 339Kb, 7 ) NLGN4Y

[159]
( , q11.2, 323Kb, 7 ) (OMIM ).
( 30). 31%
55% 91%
[160]
.
55

, - ,
, -
, ,
[161]
.

[162]
.
PDZ.

[163]
.
, - ,
,
[162]
.
56

[164]
.
,
[165]
. ,
DA, PSD-
[166]
95, .
- PSD-95 NMDA .
. ,
1, 3, 4
2 GABA
[167]
.
1, 2 3 RNA ,
, 1, 2 3
GABA ()
() ,
[168]
.
57

, NLGN3 NLGN4X, 158 ,
(c.1185_1186insT) NLGN4X
NLGN3 (p.R451C) .
,
[169]
Asperger .
350
NLGN3 NLGN4X, in vitro,
.
[170-172]
. ,
,
[170]
. p.R451C lgn1

[173]
.
, 2bp, c.1253_1254delAG, NLGN4X
13 .
, .
[174]
.
NLGN4X
[175, 176]
-: p.G99S, p.K378R, p.V403M p.R704C .
58

: 1) NLGN3 NLGN4X
[177] [178]
, 2) 4, 5 6 NLGN4X , 3) ,
p.R78W, NLGN4X ,
[179]
, 4) G>A
NLGN4X, 335bp ,
[180]
. p.R78W
, -
G335A .
3 4,
4.

[181-186]
.
2.
, NLGN4X
. , -G335A NLGN4X
[180]
- ,
NLGN4X
[187]
.
[188-191]
. ,
NLGN4X
(, , , )
59
[157, 190, 192]
, NLGN4X
[188-191]
.
. p.R451C
Nlgn3 , ,

[193]
. .

[194]
. ,
. , knockout Nlgn3
,
[195]
. Knockout Nlgn4

[196]
. , knockout ,
, .
60
)
4: ) 1.

( ). .
,
[197]
. )
4.
().
[198]
1 4 .
61

[168]
, knockout Nlgn1-Nlgn2-Nlgn3
,
[199]
- .

[200]
.
( ),
[173]
. ,
NLGN1 ,
, NLGN2
. knockout Nlgn1
, ,
NMD, Nlgn2 knockout

[173, 201]
.
62
/
()

Jamain et al. 158 NLGN3 / p.R451C 1 ASP:

2003[169] 1 & (), 1 & ();
:
NLGN4X / 1 ASP:
c.1185_1186insT 1 (A), 1 (A);
(p.D396X) :
Laumonnier et al. 9 NLGN4X / 13 (A):

2004 [174] * c.1253_1254delAG 10 , 2 & , 1 ;
(p.D429X)
Vincent et al. 2004 196 __ __ __

[184]
Talebizadeh et al. 67 __ __ __
2004 [183]
Gauthier et al. 96 __ __ __
2005 [182]
Yan et al. 2005 148 NLGN4X / p.G99S 1 proband (): ;

[176]
1 : ;
:
63
NLGN4X / p.K378R 1 proband (A): ;
:
NLGN4X / p.V403M 1 proband (A): -;

1 : ; 2 ;
: ; :
NLGN4X / p.R704C 1 proband (A): ;

1 : ; ; -
:
Ylisaukko-oja et al. 30 NLGN3 / c.222C>T 1 proband (A):

[186]
(p.Y74Y)
Blasi et al. 2006 124 __ __ __

[181]
Talebizadeh et al. 10 NLGN3 9 (): ;

2006 [177] 2 : 30 ( & ):
& 7
NLGN4X 1 ():
4
(de novo)
Lawson-Yuen et NLGN4X / 1 proband (A): , & &

al. 2008 [178] ;
4, 5, 6 1 : , & ;
: , ,
64
Wermter et al. 107 __ __ __
2008 [185]
Zhang et al. 2009 NLGN4X/ p.R87W 2 probands (A): & -

[179]

Daoud et al. 2009 96 NLGN4X / -335G>A 1 proband (A): &

[180]
(de novo)
, 169 NLGN4X / p.K378R 1 proband (A): ;

Pampanos et al. :
2009 [175]
, 40 __ __ __
Volaki et al. (under
peer review) [202]
Proband:
: , ; , Asperger; ASP, affected sib pairs
; , ; , ; , ; , Tourette.
2: 3 / 4
.
65
. : NRX1 (2p16.3), NRX2 (11q13) & NRX3 (14q31)
. (NRXN1, NRXN2 NRXN3)
, .

[203]
. ,
[204]
NMDA .
, NRX1
( 2, 2p16.3, 1.1Mb, 24 ), NRX2 ( 11,
11q13, 106b, 23 ) NRX3 ( 14, 14q31,
1.6b, 24 ). ,
RNA: mRNA -
mRNA -. ,
, - (, ,
) - (, , ),
. CNV ~1200 ,
[118]
2 , 2p16.3 .
[157, 205, 206]
NRXN1
2p16.3 NRXN1
[207]
. NRXN1 ,
[207-209]
.
[207, 210, 211]
,
66
1
. , NRXN1
Etherton et al. Nrxn1
. ,
[212]
. /
/ ,
, SHANK3
GABA .
. ,
, SHANK3
IV. CNTN4 (3p26.3) & CNTN3 (3p12.3)
CNTN4
4, ,
[213]
.
3p
[214]
. ,
67
[205, 215]
(CNVs) . ,
CNTN3 [216].
V. CNTNAP2 (7q35)
7q35
[122, 123]
. , CNTNAP2
Old Order Amish
. 2/3
[217]
.
contactin associated protein-like 2,
.
[218]

, + [219]
.
, . Arking et al.
SNP rs7794745 72 multiplex

[220]
1295 trios - . Alarcon et al.
SNP
[113]
. , CNTNAP2
, ,
, ,
.
[221]
Vernes et al. .
FOXP2, ,
CNTNAP2 . , Bakkaloglu et
al. de novo 7
68
[222]
, .
635 942 ,
8 6
. , p.869,
4010
, Scott-Van Zeeland et al.
CNTNAP2
. ,
,
[223]
.
CNTNAP2 ,
69
1.6.3.2
. RELN (7q22)
RELN
,
[224]
.
[225]
,
[226].
7q22
[119]
,
[227]
5 , .
,
[228-230]
.
[231-235]
. SNPs
[236]
, .
, ,
[133]
.
, ,
. 2 (7q36)
engrailed 2
. homeobox,
[237-239]
.
, ,
70
.
[98]
Purkinje . ,
, ,
[240-245]
, .
SNPs
. rs1861972 C rs1861973
( Asperger, -).
167 Autism Genetic Resource Exchange

[246]
(AGRE) 222 AGRE
[247]
129 National Institute of Mental Health .

[248, 249] [250]
. ( ,
[251] [252, 253]
, ) EN2 ,
.
[254, 255]
.
, 2
71
1.6.3.3
. OXTR (3p25)

[256]
(Oxytocin receptor OXTR)
3p25.
. ,
[257]
,
[258]
. ,
[259]
. ,
,
[260, 261]
. ,
, ,
[256]
, AVPR1A, .
OXTR ,
.
[262-266]
3 3
[265, 267, 268]
. ,
,
[266, 267]
.
2333
[265]
.
72
. GRIK2/GluR6 (6q21)
6q14-21
. ,
[269]
.
Asperger,
(PSD-95).

[270]
.
GRIK2
[271-275]
.
[276]
.
, GRIK2
. SLC6A4 (17q11.1-12) V. ITGB3 (17q21.32)
. 25%
[277-279]
.
(SLC6A4)
-
[280]
.
Hutterites,
[281]
.
(Quantitative trait locus) ,
73
ITGB3 (17q21.32) Leu33Pro.
, -3
. ITGB3
Leu33Pro
[282]
. ITGB3
,
[283-285]
ITGB3 SLC6A4 .
-3 ,
. , -3

[286]
. -3 Pro33

[287]
HEK293 .
ITGB3 SLC6A4.

[288]
,
[289]
.
1.6.3.4
. SLC25A12 (2q24)
2q21-q33
. SLC25A12,
/ .
74

[290]
.

[291, 292]
G GG (reverse strand) SNPs rs2056202 rs2292813 .
SNPs
[293, 294]
.
ADI-R
G rs2056202
[295]
.
SLC25A12
. ,
[296]
SNPs, . ,
SNP rs908670
[133]
AGP Consortium .
[297-300]
SLC25A12 .
. (7q31.2)
MET
[301]
7q31 .
, , ,
[302, 303] [304]
,
[305, 306] [307]
.
75
,
[308]
.
rs1858830 ( C)
[309, 310]
. ,
,
[311]
SP1 .
C.
, SNPs
1, rs38845 ( ), rs38845
[312-314]
.
. PTEN (10q23.3)
PTEN
(.. Cowden,
Bannayan-Riley-Ruvalcaba), ,
[315-318]
.
PTEN.
. , PTEN
, PTEN
[319]
SLC6A4 . , PTEN
76
[320, 321]
PTEN
. , PTEN
[322]
.
, PTEN
PTEN.
1.6.4 (CNVs)
,
[323]
.
(array-CGH),

[324, 325]
DNA .
(Copy Number Variation - CNV) DNA 1kb

[326]
. CNV , ,
. de novo
. , CNV
CNVs
. , de novo
[157, 327-330]
16p11.2 ~1%
. ,
77
, 100
[330]
. CNVs 16p11.2
[329, 331, 332]
, ,
[157]
.
CNVs 16p11.2
, o
. 16p11.2
, , ,
. ,

[333]
.
CNVs
. Pinto et al.
CNVs CNVs
,
[134]
GTPase- .
, Glessner et al.
CNTN4, NRXN1
78
[205]
. , Morrow et al. CNVs
, NLGN3/4X, NRXN1,
Protocadherin 10, CNTNAP2 CNTN3,

[216]
.
79

2.
NLGN3 (Xq13) NLGN4X
(Xq22.33) .
, NLGN3 (Xq13) NLGN4X (Xq22.33),
80
3.
3. 1
3.1.1
3 (NLGN3)
4 (NLGN4X).
169 (143
26 , 2.036.0 ; 11.15.3 ),
, 155 , 33 11 .
DSM-IV.
3.
150 (89
61 ),
81
3: 169
. O
:
(/).
/
()
1 3.4 , 18 ,
,
5 5.1 , ,
7 3.5 ,
9 4.2 , ,
10 4.0 ,
12 3.0
15 6.5 , ,
,
18 6.0 , ,

21 4.4 , ,
24 3.8 , ,

27 3.5 , ,
15 , ,
28 8.5 , , ,
,
31 3.8 , ,
32 4.0 , ,

35 3.5 ,
37 8.8 ,
, ,
40 4.5 , , ,
,
44 8.3 , , ,
46 5.8 , ,
49 ,
52 6.0 , ,
,
54 8.0 ,
58 4.0 24 ,
62 6.5 , ,
65 5.0 , ,

68 3.6 , ,
72 4.6 ,
74 3.8 10 , & ,

75 5.7 & ( ),

78 4.5 , ,

82
80 3.5 ,
82 3.6 , , ,
, &
84 4.7 ,
86 5.6 , ,
89 9.8 , ,
90 12.4 , , ,
,
92 4.8 , ,
94 3.2 , ,

96 3.3 , , 2

98 2.0 , , ,
, 2
100 11.0 ,
101 14.5 , ,
,
102 8.5 ,
103 15.0 & , ,
104 11.0 , , ,

105 4.5 , ,
106 2.5
107 3.0 8 ,
& ,
108 6.0 , ,
, ,
109 12.5 , , ,
,
110 3.0 , ,
,
111 4.3 , ,

112 6.0 , , &

113 6.0 , , , MRI
114 6.0 & , ,

115 3.5 &
116 3.0 ,
117 2.5 , ,
118 5.5 ,
119 5.0 ,
120 14.0 , ,
121 4.0 , ,
122 2.5 , ,
, .
123 2.4 , ,
124 12.0 , ,
125 9.0 ,
126 5.0 , ,
127 4.5 , & ,
83
128 3.2 ,
129 3.8 , ,
130 4.0 18 , ,
,
131 3.5
132 4.0 ,
133 4.8 , , ,
134 8.0 ,
135 5.0 & , , , ,
3.5
136 3.0 ,
137 3.0 , ,
138 6.0 ,
139 9.4 , ,
, , , , MRI:

141 3.0 , ,

142 5.0 13 , ,

143 22.0 , ,
144 7.0 , ,
,
145 4.3 , , ,
146 4.5 , , ,

147 4.0 ,
148 3.5 , ,

149 2.5 , ,
150 4.0 ,
151 4.5 , , ,

152 4.5 , ,
153 4.5 , ,
,
154 3.0 ,
155 4.0 , ,
Asperger
156 9.4 , ,
157 14.0 ,
158 5.0 , ,

159 1.8 &
160 3.3 , ,

161 3.5 , , ,
162 3.0
163 3.5 ,
164 2.2 , ,
11 , ,
165 4.7 , ,
166 3.0 , ,
84
167 3.0 , ,
168 9.0 , ,
169 5.0 ,
170 4.0 & ,
171 2.5 , , MRI:

172 3.3 t(4;9)(p15.3;q13) ,

173 7.5 ,
174 4.0 ,
175 4.0 &
176 4.5 , ,
177 18.0 ,
178 4.0 ,
179 3.0 & , ,
,
180 2.0 , ,
181 2.0 , ,

182 3.0 ,
183 2.6 , , , MRI
184 2.5 12 , ,
, ,
185 15.0 , , ,
, ,
186 7.0
187 3.5 , ,
188 3.0 , ,
189 3.5 , ,
190 3.0 18 ,
191 3.0 ,
192 14.0 , & ,

193 4.0 ,
195 4.0 , ,

197 4.0 , ,
199 3.0 ,
200 12.0 ,
202 36.2 , ,
206 9.7 , , , ,
,
208 3.0 , & ,

211 6.2 ,
213 4.9 , ,

215 2.0 , ,
&
217 4.3 , ,
218 5.4
220 8.3 , , ,

85
222 2.9 , ,
224 9.7 , , ,

226 4.5 , , ,
MRI ( )
228 2.6 , , ,
,
230 5.0 , , ,
,
232 5.6 , ,
, , ,

343 6.0 , ,
346 3.8 , ,
,
348 5.9 , ,
,
350 16.0 &

352 7.9 , , ,
Asperger
354 8.1 , ,
356 2.5 ,
358 7.6 , , ,

359 5.5 ,
360 13.3 , , ,
, , &

362 4.0 ,
364 3.5 , , ,
366 5.5 , ,
368 4.0 , ,
369 2.5 ,
& 1.5/

370 9.9 , , &
,
372 6.5 ,
86
3.2
3.2.1 ,
* ( PCR): ) ABI Verity ) Techne TC-412 ) Biometra
T3000
* : ) Eppendorf MiniSpin plus ) ultifuge 3S-R, Heraeus ) Hettich
Universal 320 Centrifuge
* : WAVE MD
System (Transgenomic)
* : MegaBACE 1000 DNA
Sequencing System (GE Healthcare)
* : Thermo Scientific, Owl Separation Systems
* : NanoDrop 1000 (Thermo Scientific)
* : GDS-8000 Ultra-Violet Products Ltd
(UVP Inc.)
* H : Libror EB-32000 (Shimadzu)
* Gilson 0.2L
1000L
* Eppendorf 10L
200L
* Orbital Shaker plates
* (sterile, RNase free, DNase free)
* PCR 200L (sterile, RNase free, DNase free)
* Eppendorf 1.5mL (sterile, RNase free, DNase free)
* 96 PCR 200L (sterile, RNase free, DNase free)
87
* universal 15 50mL
3.2.2 DNA
DNA
3mL EDTA ,
. DTA,
(.. )
DNA , PCR.
DNA : DNA,
QIAmp DNA Mini Blood Kit QIAGEN
BioRobot M48, MagAttract DNA Blood M48 Kit
QIAGEN.
QIAmp DNA Mini Blood Kit, ,
(AL buffer). 56C 15
DNA. ,
, DNA QIAmp,
(, RNA )
. DNA ( 5).
88
, 2,5 105 mL 16g
DNA.
5: DNA
DNA,
QIAmp DNA Mini Blood Kit
QIAGEN.
MagAttract DNA Blood M48 Kit
DNA ,
MagAttract
89
, .
DNA ,
. DNA
, DNA. ,
DNA . DNA
. 6
MagAttract DNA Blood M48.
6: MagAttract DNA Blood M48.
90
3.2.3
(Polymerase Chain Reaction -
PCR), 1986 K. Mullis

[334]
, in vitro
DNA
DNA (Taq polymerase,
Thermus Aquaticus). H PCR , ,
DNA, 100
2000, .
( 1109) DNA,
(1-2 ). PCR DNA
DNA 53,
o DNA . (primers)
, DNA .
DNA DNA
, DNA ,
5 (dNTPs:
dATP, dCTP, dGTP, dTTP).
DNA .
MgCl2, Mg2+
91
dNTPs
DNA
, :
: 18- 24
DNA ( DNA) 20
(GC) 45-55%. H
, 3 ,
(primer dimer formation).
PCR
[335] [336]
IDT Primer-BLAST .
92
PCR ,
20-30 ( DNA):
1. DNA (93C-97C) 30-90
sec.
2.
-,
(50C-70C) 30 sec-3 min.
3. ,
72C ( DNA
dNTPS, ) 30 sec-3 min.
( bp)
DNA.
, 220
20 . PCR
93
7: PCR (: http://bio1152.nicerweb.net/Locked/media/ch20/).
94
3.2.4 PCR
DNA
. ,
DNA
PCR ARMS PCR.
(tanks),
DNA , ,
PCR ,
(=254 nm),
DNA.
(SeaKem GTG Agarose, Cambrex Bio Science Rockland, Inc.)
, (1 : 89mM Tris HCl, 89mM Boric acid,
2.5mM EDTA) 2%.
5 l/100 ml ,
(~37-40C).
(trays),
DNA .
95
DNA (6X )
1 l / 5 l DNA.
174 Hae III () (New England Biolabs Inc.).
DNA
100-120 Volt
30-40 1 TBE.
DNA .
3.2.5 DNA
DNA (Whole Genome Amplification, WGA)
DNA
REPLI-g Mini Kit (Qiagen).

[337, 338]
(Multiple Displacement Amplification, MDA) . MDA
. DNA
29 (
DNA )
. 29 DNA
DNA 100 b
DNA >10ng / 2.5L
10g / 50L 10b ( 2-100b).
WGA 8 9.
96
WGA
c.222C>T p.R451C NLGN3,
c.1185_1186insT NLGN4X x
[169, 186]
.
ARMS PCR
dHPLC.
8: DNA MDA .
) MDA : 29 DNA , ,
, DNA-
) DNA
. 29 DNA DNA
. 29
DNA - DNA
. .
DNA DNA
. (: www.biocompare.com)
97
9: DNA REPLI-g Mini kit (Qiagen).
3.2.6 ARMS PCR
ARMS PCR (Amplification refractory mutation system PCR),
,
[339]
.
DNA
3 DNA .
98
,
(wild type)
(mutant).
, (wild type)
(common). ,
3 ,
DNA.
DNA-
DNA- ( 10).
DNA PCR
PCR .
(control
primers) DNA,
PCR .
99
10: .
400bp . ,
245bp -,
, -. M= 100bp
(: http://jmg.bmj.com).
3.2.6.1 ARMS PCR c.222C>T
(p.Y74Y)
ARMS PCR c.222C>T
(p.Y74Y) 2 NLGN3. 169
. ,
PCR 2% 150ml TBE (1X).
100

10 l Hotstaraq DNA MasterMix (Qiagen)

1.5 l forward (10 pmol/l)
1.5 l reverse mutant/wild type (10 pmol/l)
0.3 l forward control (10 pmol/l)
0.3 l reverse control (10 pmol/l)
4.4 l dH2O
1 l DNA (80ng/L)
: 20l

Forward (5 3) Forward (5 3) Reverse (5 3)
(bp)
Mutant: Wild type: Common:

138
ATACCTGGGGGTGCCTTAT ATACCTGGGGGTGCCTTAC ACAGCTGTGTGGATGTTCTG
Control: Control:
328
AGTGCTGCAAGAAGAACAACTACC CTCTGCATCATGGGCAGTGAGCTC

1 95 C 15 min x1

2 DNA 95 C 1 min

3 59 C 1 min x 30

4 72 C 1 min

5 72 C min x1
101
3.2.6.2 ARMS PCR c.-705 A>G
ARMS PCR c.-
705>G 1 variant 1 NLGN4X 150 .
. PCR
2% 150ml TBE (1X).

0.25 l reverse mutant/wild type (5 pmol/l)
3 l dH2O
1l DNA (80ng/L)
: 10l

Forward (5 3) Reverse (5 3) Reverse (5 3)
(bp)
Common: Mutant: Wild type:

396
CAAAGGATGGAAAGCCTCACT CTTCTCCCTGTACTGCCGAC CTTCTCCCTGTACTGCCGAT
Control: Control:
296
CTATGGGCATTGGTTGTC AAAAGCAGTGGTAGTCCAG

1 95 C 15 min x1

2 DNA 95 C 1 min

3 58 C 1 min x 32

4 72 C 1 min

5 72 C 10 min x1 102
3.2.6.3 ARMS PCR c.-206G>C
ARMS PCR c.-
206G>C 2 NLGN4X 150 .
. PCR 2%
150ml TBE (1X).

0.25 l reverse mutant/ wild type (10 pmol/l)
3 l dH2O
1l DNA (80ng/L)
: 10l

Forward (5 3) Reverse (5 3) Reverse (5 3)
(bp)
Common: Mutant: Wild type:
197
CGTGGAAGAGCCAGCCAGTGT ATTGCAAGGAGGCAGCCGTCCG ATTGCAAGGAGGCAGCCGTCCC
Control: Control:
358
CACCTGGGATAGCTTTGCTG GCACCAGCTAGAGAAGCAAG

1 95 C 15 min x1

2 DNA 95 C 1 min

3 58 C 1 min x 32

4 72 C 1 min

5 72 C 10 min x1
103
3.2.6.4 ARMS PCR c.1597A>G (p.K378R)
ARMS PCR c.1597A>G
(p.K378R) 5 NLGN4X 150 .
. PCR
2% 150ml TBE (1X).
10 l HotstarTaq DNA MasterMix (Qiagen)

0.8 l reverse mutant/ wild type (5 pmol/l)
1 l MgCl2 (25mM)
5.6 l dH2O
1l DNA (80ng/L)
: 20l

Forward (5 3) Forward (5 3) Reverse (5 3)
(bp)
Mutant: Wild type: Common:

413
ACCAAGGGGAAGGCCCGAG ACCAAGGGGAAGGCCCGAA ACTGAAGAGCTCGGTGGGAC
Control: Control:
254
GAACGCCACACACTTTCC ACGTCCCGTGTGTTGGT

1 95 C 15 min x1

2 DNA 95 C 1 min

3 60 C 1 min x 35

4 72 C 1 min
104
5 72 C 10 min x1
3.2.7
(dHPLC)
(denaturing High
Performance Liquid Chromatography, dHPLC) ,
DNA
DNA PCR
( )
. .
. DNA
DNA
DNA .
, .
( ,
, , ),
[340]
DNA .
. WAVE MD DNASep
-. PCR ,
105
Buffer A (0.1M Triethylammonium acetate (TEAA))
DNA ( 11). DNA DNA
(Buffer A Buffer B (0.1M TEAA 25% acetonitrile) (Transgenomic))
. Buffer B
DNA . ,

[341]
. PCR
WAVEMAKER 3.4.
DNA UV
(E 12).
11:
WAVE MD (:
Transgenomic)
106
12: PCR
(: Transgenomic)
. dHPLC
, PCR .
3.2.7.1 dHPLC 6 v NLGN3 5
v NLGN4
dHPLC v NLGN3
5 v NLGN4 169 .
, ,
107
.
1: PCR
dHPLC,
Optimase (Transgenomic Inc., NE, USA).
Optimase WAVE
MD PCR.

[342, 343]
.
dHPLC

Forward (5 3) Reverse (5 3)
(bp)
NLGN3
TGTATGGCTATCCTGAGGGTAAGG TTCATGAGGCTCTGGCAGTGATGA 226
6
NLGN4X
AAGGCGAGTTCCTCAACTACGACA TCAGTAAAGAGAGCCACCAGGGTT 262
5
1 l Optimase Polymerase (2.5 units)

5 l 10X Reaction buffer (containing 1.5mM MgSO4)
3 l MgSO4 (25mM)
5 l dNTPs (200 M dNTP)
2 l forward (10 pmol/l)
2 l reverse (10 pmol/l)
30 l dH2O
2l DNA (80ng/L)
: 50l
108
Touchdown PCR

1 95 C 2 min x1

2 DNA 95 C 30 sec
x 15
3 69.2 C 62.2 C 30 sec (-0.5 C/)

4 72 C 30 sec

5 DNA 95 C 20 sec
6 62.2 C 1 min x 20

7 72 C 30 sec

8 72 C 4 min x1
2: PCR
2%.
3:
PCR, ,
2 1.

PCR
1 96 C 10 min x1

PCR x 450
2 96 C 51 C 5 sec
(-0.1 C/)
109
4: dHPLC
PCR : 0.9ml/min
6 NLGN3 : 63.5C
5 NLGN4 ( ): 62.5C
( ): 62.0C
3.2.8 DNA
DNA (DNA sequencing) ,
DNA.
, .
DNA Sanger,
. ,
(dNTPs) -
(ddNTPs). 2, 3-
2 3 , ,
. , DNA
( 5
ddNTP 3 ),
( 3 ). , ,
ddNTPs
. DNA 13.
110
sequencing
DNA, , DNA
, (, , ,
),
, . dNTPs: ddNTPs
DNA ,
5 3 . 5 , 3
ddNTP dNTP
ddNTP .
13: DNA Sanger (: http://dnasequencing-

humandnasequence.blogspot.com).
111
3.2.9 sequencing MegaBACE
NLGN3 NLGN4X
MegaBACE 1000 (GE Healthcare, Piscataway, NJ,
USA) DNA Sequencing System ( 14).
, MegaBACE,
, Instrument Control Manager Sequence Analyzer
. ddNTPs
laser. ,
. DNA
DNA .
14:
MegaBACE
DNA (GE Healthcare).
DNA , ,
112
NLGN3 NLGN4 4 5.
DNA.
MegaBACE
, . 15
DNA.
15. DNA.
3.2.9.1 DNA
PCR
DNA Nanodrop.
. Pulse vortexing 10sec
113

2O.
DNA :
1. ng/l PCR 10ng/l

100ng/l.
2. A260/A280 1.8 2 DNA
.
3. 260/230 >2 DNA
( t
DNA >1.5).
3.2.9.2 PCR sequencing
NLGN3 NLGN4X
() NLGN3 (NM_018977) and NLGN4X (NM_020742)
5 (5-UTR): ) 1 NLGN3
) NLGN4: 1 variant 1 (
NM_020742) 1 variant 2 ( NM_181332), 3
NM_0181303 NLGN3. NLGN4X
NLGN4Y ,
NLGN4X.
40
114
PCR
12.5l Hotstaraq DNA MasterMix (Qiagen) *

2l forward (5 pmol/l)
2l reverse (5 pmol/l)
8.5 l H2O
1l DNA (80ng/L)
: 25l
* 1.25 units HotStarTaq DNA polymerase, 0.75mM MgCl2 100M dNTP
, 2
4 5.
PCR

1 95 C 15 min x1

2 DNA 95 C 1 min
x 15
3 65C 58 C 30 sec (-0.5 C/)

4 72 C 1 min

5 DNA 95 C 1 min
6 58 C 30 sec x 25

7 72 C 1 min

8 72 C 10 min x1
115
4: E sequencing NLGN3

E Forward / reverse (53) PCR
(bp) MgCl2 (25mM)
[M13f]- tggcacaaaaggagttaatgg / TD 65-58 x15 cycles + 58 x25 cycles (1', 30'', 1') +
1 284 -
[M13r]- agtggaggagcctgggatt 0.7l 7-deaza-dGTP (5mM)
[M13f]- ctgggcatgtgaaacctctc /
2 849 TD 65-58 x15 cycles + 58 x25 cycles (1', 30'', 1'15'') -
[M13r]- catgcaagccacaaacacag
[M13f]- ctgcagtcatgctgtttttga / TD 65-58 x15 cycles + 58 x25 cycles (1', 30'', 1') +
3 256 -
[M13r]- ggaacagaaacacaccaacg 0.5l 7-deaza-dGTP (5mM)
[M13f]- agagcagctcagctcttgg / TD 65-58 x15 cycles + 58 x25 cycles (1', 30'', 1') +
3* 253 -
[M13r]- tgggctacttggaggaagg 0.5l 7-deaza-dGTP (5mM)
[M13f]- cacctgggatagctttgctg / TD 65-58 x15 cycles + 58 x25 cycles (1', 30'', 1') +
4 358 -
[M13r]- gcaccagctagagaagcaag 0.5l 7-deaza-dGTP (5mM)
[M13f]- tattcccacctcccctgttg / TD 65-58 x15 cycles + 58 x25 cycles (1', 30'', 1') +
5 382 -
[M13r]- aagagagctggccgattcc 0.5l 7-deaza-dGTP (5mM)
[M13f]- cagcctcagtgacaaaggaa / TD 65-58 x15 cycles + 58 x25 cycles (1', 30'', 1'15'')+
6 966 -
[M13r]- ggaagggatatgatggaagagg 0.5l 7-deaza-dGTP (5mM)
[M13f]- aggtttggctgtcagaggaa / TD 65-58 x15 cycles + 58 x25 cycles (1', 30'', 1'15'')+
7 990 -
[M13r]- tgcatgtgttcctggatctg 0.5l 7-deaza-dGTP (5mM)
* NM_0181303
116
5: E sequencing NLGN4X

Forward / reverse (53) PCR MgCl2
(bp)
(25mM)
[M13f]- agctatttgaacggctctgg / TD 68-61 x15 cycles + 58 x25 cycles (1', 30'', 1') + 0.5l
1 (variant 1)a 586 1l
[M13r]- cctcgaaacccacacacac 7-deaza-dGTP (5mM)
[M13f]- ggagacagcaggacctctc /
1 (variant 2)b 471 TD 67-60 x15 cycles + 58 x20 cycles (30'', 30'', 40'') -
[M13r]- tatctgcagtgaggctttcc
[M13f]- gccagtgttctaggtggtcg / TD 65-58 x15 cycles + 58 x25 cycles (1', 30'', 1'15'')+
2 910 1l
[M13r]- aaaccctcctagcaaatctctcta 0.5l 7-deaza-dGTP (5mM)
[M13f]- aatttagcattggtgagtcagtgt /
3 285 TD 65-58 x15 cycles + 58 x25 cycles (1', 30'', 1') 1l
[M13r]- cgtcaaaacgagaagtggac
[M13f]- tgggggtgagagttgagga /
4 397 TD 65-58 x15 cycles + 58 x25 cycles (1', 30'', 1') 1.75l
[M13r]- caggacatgcatctgagatatg
[M13f]- ctcacatgcctgagagacaat / TD 68-61 x15 cycles + 58 x25 cycles (1', 30'', 1'15'') +
5 972 1l
[M13r]- gtggcagtagaagcaacacc 0.5l 7-deaza-dGTP (5mM)
[M13f]- ttattggtttaagataatttcacg /
6 957 TD 63-56 x15 cycles + 58 x25 cycles (1', 30'', 1'30'') 1l
[M13r]- ggacaaaaacattcctggtc
a
NM_020742.2
b
NM_018977
13 forward : 5 GTAAAACGACGGCCAGT 3
13 reverse : 5 CAGGAAACAGCTATGAC 3
117
3.2.9.3 PCR
. MinElute 96 UF PCR Purification plate (Qiagen)
PCR >250bp
1. PCR 25l, blanks
PCR 40l water for injection
1-2 MinElute 96 UF PCR Purification
plate.
2. PCR (-800mBar) 20-30
BioRobot 3000.
3. , .
4. 20l 2
5. plate orbital shaker
1000 15 .
6. T DNA ,
, PCR plate 96 strips.
. PCR
DNA PCR
Nanodrop.
. PCR
sequencing 100-200fmoles
PCR. PCR
blanks PCR , ng/l,
118
fmol/l,
http://sciencelauncher.com/MWcalc.html
3.2.9.4 sequencing

Reagent premix* 4 L
13 Forward
0.5 L
Reverse (5 )
Template DNA 1 L
H 2O 4.5 L
Total Volume 10 L
*DYEnamic ET terminator reagent premix (MegaBACE, GE Healthcare)
sequencing
95 0C 20 sec
50 0C 15 sec x 25 cycles
60 0C 1 min
3.2.9.5 sequencing
universal 15ml, EtOH/NH4Ac
DNA sequencing :
1 plate
1 96
EtOH (100%) 27.5 l 4.0 ml
NH4Ac (7.5M) 1.0 l 145.4 l
119
1.
2. ( 10l) 8 28.5l .
3. plate.
4. plate 30min .
5. plate 3500rpm 30min,
4C.
6. plate plate
( )
1400rpm 2min 4C.
7. 100l EtOH 70% .
8. 1400rpm 3min 4C.
9. plate plate
1400rpm 3min 4C.
10. plate 10min.
11. 10l Loading buffer (70% formamide,
1mM EDTA, (MegaBACE, GE Healthcare) 20
12. To plate RUN MegaBACE
MegaBACE, :
(injection): 3kV 40
: 8kV 105
BioEdit
Sequence Alignment Editor 7.0.5.3 (Tom Hall, Ibis Biosciences, Carlsbad, CA,
USA).
120
3.2.10
in
silico .
Polyphen (http://genetics.bwh.harvard.edu/pph/) SIFT
(http://sift-dna.org).
NLGN4X
: NLGN1, NLGN2,
NLGN3 NLGN4Y. online
ClustalW DNA
(http://www.ebi.ac.uk/Tools/msa/clustalw2/). ,
NLGN4X 34 (Eutherian
mammals),
Ensembl (release 64) (http://www.ensembl.org). ,
(splicing) Human Splicing Finder v2.4.1

[344]
(http://www.umd.be/HSF/) . ,
, NLGN4X,
MatInspector Genomatix suite

[345]
(http://www.genomatic.de/matinspector.html) .
121
4.
4.1 ARMS PCR c.222C>T
(p.Y74Y)
169 ARMS PCR
c.222C>T (p.Y74Y) 2 NLGN3
3.2.5.1 .
2% ( 16). C
( 17).
16: 1.5% 1.5% Nusieve ARMS

PCR c.222C>T (NLGN3, 2). (1-5)
c.222C>T (6), : 100bp , :
(control ), : (mutant-common ).
122
1 2 3 4 5 6
17: 2% ARMS PCR

c.222C (NLGN3, 2). (1-5)
c.222C>T (6), : 174 , : (control ), :
(wild type-common ).
4.2 dHPLC
NLGN3, 6
169 dHPLC
p.R451C 6
NLGN3 3.2.6.1
. ,
p.R451C
18
(NL). ,
123

p.R451C
( 19).
18:
(NL).
19: (NL)
p.R451C (MUT).
(%) MUT NL.
124
4.3 dHPLC
NLGN4, 5
169 dHPLC
c.1185_1186insT, c.1253_1254delAG
5 NLGN4
3.2.6.1 .
40,
. 168
dHPLC 40
( 20)
( 21)
3.2.7.1 . .
c.1597 A>G (p.K378R)
PCR
, ARMS PCR.
125
20: 40
p.K378R ( ), (
) ( ).
( )
( ).
126
NLGN4X (Xp22.33)
21: NLGN4X
5 40 .
c.1597 . G
(p.K378R), B /G (p.K378R), C .
p.K378R , Polyphen SIFT,
NLGN4X . p.K378
( 22),
127
[346]
. , p.R378
22: p.K378
( Polyphen).
128
4.4
NLGN3 NLGN4
NLGN3 NLGN4
40 ,
3.2.7 3.2.7.1.
NLGN4X: ) c.1597A>G (p.K378R)
( 40
), )
c.-206G>C 197, ) SNP
rs111953947 c.-705A>G 141 179 )
SNPs dbSNP. NLGN3
SNP dbSNP.
6.
c.-705A>G c.-206G>C
PCR
129
/ SNP id

a
c.2272 G>A
NLGN3 7 3/40 rs17857401
(p.G758S)
NLGN4X 1 rs111953947
c.-705 A>G b * 2/40 5/150
variant 1 ( )
NLGN4X 1 b
c.-577_-576del 29/40 rs72413786
variant 1
NLGN4X 1
c.-518 G>A b 7/40 rs2290487
variant 1
NLGN4X 1 b
c.-431G>C 16/40 rs2290488
variant 1
b
NLGN4X 2 c.-206G>C 1/40 3/150
b
c.933 C>T
NLGN4X 5 11/40 rs7049300
(p.T311T)
c.1597A>G b [175, 176]
NLGN4X 5 1/40 0/150
(p.K378R)
c.1777 C>T+
11/40 rs3747333,
NLGN4X 6 c.1779 C>G b
rs3747334
(p.L593L)
NM_018977
b
NM_020742.2
*
6: DNA NLGN3 NLGN4X.

.
c.-705A>G 5 (upstream sequence)
NLGN4X, 1 variant 1,
: 1) 179,
( 23), 2) 141,
( 24).
5 (4 , 1 ) 150 ,
ARMS PCR.
130
NLGN4X (Xp22.33)
23: NLGN4X ( 1 1)
179 . c.-705
. G, B /G,
.
131

Iroquois homeobox 6
24: NLGN4X ( 1 1)
141 . c.-705
. /G, B G,
.
NLGN4X
(NLGN1, NLGN2,
NLGN3, NLGN4Y) c.-705A
NLGN4X NLGN1 ( 25).
NLGN4X 34
132
( 26).
. In silico ,
Human Splicing Finder,
RNA
SRp40 and SC35 / .
MatInspector
c.-705A>G ,
Iroquois homeobox 6 (atataTATGtatc)
NLGN1
NLGN4Y
NLGN2
NLGN3
NLGN4X
NLGN1
NLGN4Y
NLGN2
NLGN3
NLGN4X
NLGN1
NLGN4Y
NLGN2
NLGN3
NLGN4X
25:
NLGN4X
(NLGN1, NLGN2, NLGN3, NLGN4Y). c.-705 NLGN4X
( ClustalW).
133
26:
NLGN4X 35 . c.-705
NLGN4X (
Ensembl).
134
, c.-206G>C,
No 197, ( 27).
3 (2 , 1 ) 150 ,
ARMS PCR. c.-206G
, NLGN4X NLGN4Y (
28). 35 ,
c.-705A,
( 29). In silico ,
Human Splicing Finder,
SC35 SRp40
(hexamer FAS-ESS, exonic splicing silencer) .
135
NLGN4X (Xp22.33)
27: NLGN4X ( 2) 197

. c.-206
. C, B C/G,
G.
136
NLGN4
NLGN4
NLGN3
NLGN1
NLGN2
NLGN4
NLGN4
NLGN3
NLGN1
NLGN2
NLGN4
NLGN4
NLGN3
NLGN1
NLGN2
28:
2 NLGN4X
(NLGN1, NLGN2, NLGN3, NLGN4Y). c.-206 NLGN4X
( ClustalW).
137
29: 2
NLGN4X 35 . c.-206
NLGN4X (
Ensembl).
138
5.
, , ,
. ,
-
[347]
. MET
CNTN3 , RELN
SHANK3, CNTNAP2, NLGN3, NLGN4, NRXN1, CDH9 CDH10
, ,
, NLGN3 NLGN4X .
Xp22
[348-351]
NLGN4X . ,
139
[131, 352, 353]
, CNVs
[157,
SHANK3, NLGN NRXN
205, 216, 354, 355]
.
O ,
. H

[287]
, .
[169] [174]
Jamain et al. Laumonnier et al.
NLGN3 NLGN4 ,
, ,
. ,
NLGN3 NLGN4 .
169
, 2.0 36.0 . 40
, 2 Asperger 127
140

155 169 (92%).
81 169 (48%),
(11/169, 6.5%)
(8/169 = 5%).
19/169 (11%) 22/169 (13%).
10%
22%. -,
27%, 24% 21% , .
169 ,
dHPLC : 1)
, DNA, 2)
, 3)
4) (>99%),
[356-358]
.
2 : 1 ( :
),
, .
2 : 1, 4 : 1 ( :
) ( 19,
20% 80% ). 2 : 1 ,
141

dHPLC 6 NLGN3
5 NLGN4X,
: 1) p.R451C, 2) c.1185_1186insT
[169]
Jamain et al.
Asperger 3) c.1253_1254delAG (NLGN4X, 5)

[174]
Laumonnier et al. / .
(169 ) ARMS PCR
c.222C>T (p.Y74Y) 2 NLGN3,

[186]
.
150 c.-
705A>G, c.-206G>C, c.1597A>G.
. ,
dHPLC ARMS-PCR
WGA. WGA
DNA MDA
. DNA
. , 29 DNA
142
3-> 5
[359]
DNA .
, 40 169
, sequencing NLGN3 NLGN4X
. sequencing
dHPLC
ARMS PCR, (p.R451C, c.222C>T
NLGN3, c.1185_1186insT, c.1253_1254delAG NLGN4). ,
NLGN4X : ) , c.1597A>G 5,
[175]
, p.K378R , )
, c.-206G>C 5 ( 2) )
SNP, rs111953947, c.-705A>G (
6). ,
online .
online NLGN4X,
35 , .
,
[360]
.
Ensembl.
: (Gorilla gorilla), (Pan troglodytes), (Felis catus),
(Canis familiaris).
143
c.1597>G (p.K378R), 40
3 ,
, . 16
, , ,
. (46,).
41 43
, c.1597A>G (p.K378R),
Yan et al.
4 . , ADI-R
: 20 , 12 5
[176]
, .
2 . ,
. ,
NLGN4X ,
. Yan et al.
, p.K378R ,
[176]
.
p.K378R ,
Polyphen SIFT,
NLGN4X ,
150 (89
144
61 , 211 ). ,
48 Yan
et al.
p.R378
, 3 (Danio rerio
, Tetraodon nigrovidiris spotted green pufferfish, Oreochromis niloticus
, 22,
3 . , ,
4. , p.K378
( 22),
( 30),
[361]
4 .
,
[197]
.
NL1, NL4 Nrx1b ,
, p.K378
Nrx1b ( 4). ,
Nrx1,
, . (R)
() ,
. , ,
145
, ,
[197, 362]
.
.
[176]
Yan et al. ,
p.K378R
, .
146
30:
. -
. .
-
[197]
( : Chen et al. 2008 ).
147
c.-206G>C ,
4 ( 197) ,
, .
. 2
NLGN4X 5 .
. 3 150 , 2
. ,
c.-206G>C,
NLGN4X
(NLGN1, NLGN2, NLGN3, NLGN4Y).
NLGN4X NLGN4Y
( 28),
. ,
NLGN4X 34 (
29). ,
. in silico
, Human Splicing Finder.
, c.-206G>C, SNP dbSNP
148
rs150495370,
, rs111953947 , c.-705>G
. 3 ( 179) ,
, , ,
, 3 ( 141) ,
, , .
dbSNP, in silico
Iroquois homeobox 6 (atataTATGtatc) c.-
705A>G .
(http://www.genomatic.de/matinspector.html). ,
, dbSNP
( 141)
5 150 (4 ),
( 25) 35
149
( 26).
. ,
Iroquois homeobox 6 ,
NLGN3 NLGN4X
,
[176-178, 180-186]
.
,
[169, 174, 179]
. ,
NLGN3 NLGN4X
/ , <1%
[363]
.
( ),
( 2). , NLGN3 NLGN4X
Tourette, , , ,
[176, 178, 192]
. , ,
, .
- ,
150
[364, 365]
, .
--SHANK3
, (cadherins, protocadherins),
(CNTN3, CNTN4, CNTNAP2),
( CNVs,
, , )
GABA
[140]
. ,

[366]
.
NLGN3 NLGN4X
,
[367]
GTP/Ras .
. ,
151
.
[367]
.
NLGN3 NLGN4,

[65, 76]
, .
, ,
, , , 1 2,
152
[368-371]
Crohn . ,
. T ,
153
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: 210 9953728 / 6932322103

9.1998 - 6.2002: BSc in Biological Sciences with Honours in Genetics

1998: International Baccalaureate, -

9.2009 7.2011: International

1. Volaki Konstantina, Pampanos A, Kitsiou-Tzeli S, Vrettou C, Oikonomakis V,

2. Pampanos A, Volaki Konstantina, Kanavakis E, Papandreou O, Youroukos S,

1. Volaki K, Pampanos A, Kanavakis E, Oikonomakis V, Vrettou C, Papadaki-

3. Volaki K, Pampanos A, Papadaki-Papandreou O, Thomaidou L, Giouroukos S,

4. Volaki K, Pampanos A, Papadaki-Papandreou O, Giouroukos S, Thomaidou L,

5. Pampanos A, Volaki K, Papadaki-Papandreou O, Thomaidou L, Giouroukos S,

6. Pampanos A, Volaki K, Thomaidou L, Giouroukos S, Papadaki-Papandreou O, Kitsiou-

: Certificat Pratique de Langue Franaise (1er Degr), Universit de Paris

c.222C>T (p.Y74Y) 2 NLGN3. ,

DNA NLGN3 NLGN4X.

SNP, rs111953947, c.-705A>G, .

Autism belongs to the category of neurodevelopmental disorders and is

characterized by difficulties in social interaction and communication as well as

genetic, neuroanatomic, environmental and various pathological conditions, which interact

Mutations in two X-linked neuroligin genes, NLGN3 (Xq13.1) and NLGN4X

(p.Y74Y) in exon 2 of NLGN3. In addition, 40 patients with diagnosis of autistic disorder

substitution mutation, c.1597A>G in exon 5, leading to the amino acid substitution

exon 2, c) one non-validated SNP, rs111953947, in the promoter. Analysis performed

predicts that the above variants are benign or polymorphisms.

literature, in addition to the lack of association of mutations with specific phenotypes, do

ADI-R Autism Diagnostic Interview- Revised

ADOS-G Autism Diagnostic Observation Schedule-Generic

AGP Autism Genome Project

AGRE Autism Genetic Resource Exchange

ARMS PCR Amplification refractory mutation system PCR

ASD Autism Spectrum Disorders

ASP affected sib pairs

CNVs Copy Number Variations -

dHPLC denaturing High Performance Liquid Chromatography

dNTP Deoxyribonucleotide triphosphate

DSM Diagnostic and Statistical Manual of Mental Disorders

fMRI Functional magnetic resonance imaging -

GWAS Genome-wide association studies

ICD International Classification of Diseases

PCR Polymerase chain reaction

PSD-95 Post-synaptic density protein 95

SNP Single nucleotide polymorphism

WGA Whole Genome Amplification

(Autism Diagnostic Observation Schedule-Generic (ADOS-G)

Interview- Revised (ADI-R).

DSM-IV-TR ICD-10. ADOS-G

1980, 4-5 10000

20.6/10000 ( 7.2 40.5/10000),

Asperger 6/10000. - 3-4:1.

Developmental Disabilities Monitoring Network) 57% o

Wing L. Gould J. (1979)

Rett, Prader-Willi Angelman

, Diffusion Tensor Imaging (DTI)

: (i) Purkinje, (ii)

association studies - GWAS) , (Linkage studies),

(Copy Number Variants CNVs).

780 (3101 ) 1204

6 SNPs (Single nucleotide polymorphisms)

synaptic density protein 95),

22q13 22q13 Asperger

(donor splice site)

. : NLGN3 (Xq13.1) & NLGN4X (Xp22.33)

3q23.32, 885Kb, 7 ), NLGN2 ( 17, 17p13.2,

Vincent et al. 2004 196 __

Blasi et al. 2006 124 __