THEJOURNAL

OF B I O ~ I C CHEMMTRY
AL
Vol. 268,No. 35,Issue of December 15, 26033-26036, 1993
0 1993 by The American Society for Biochemistry and FXblecular Biology Inc.
Printed in CS.A.

Minireview
Type IV Collagen: Structure,
Gene Organization, and
Role in Human Diseases
MOLECULAR BASIS OF GOODPASTURE AND
ALPORT SYNDROMES AND DIFFUSE
LEIOMYOMATOSIS*
Billy G. Hudson$, Stephen T.Reedersl, and
Karl Tryggvasonll
From the Uepartment of Biochemistry and Molecular
Biology, University of Kansas Medical Center, Kansas
City, Kansas 66160,the Howard Hughes Medical
Institute, Yale University School of Medicine, New
Haven, Connecticut 06536-0812,a n d the Wiocenter a n d
Department of Biochemistry, University of Oulu,
FIN-90570 Oulu, Finland
Basement membranes (BMs)' are thin sheetlike extracellular
structures that compartmentalize tissues.They provide substrata
for organ cells and important signals for differentiation, maintenance, and remodeling of tissues. In the renal
glomerulus, the BM
also contributes to themolecular sieve for the selective removal of
small molecules from blood. The BM is composed of several proteins specific for these structures such as type IV collagen (l),
laminin, proteoglycan, and entactinhidogen (2). BM function is
altered in a number of acquired and genetic diseases, exemplified
by Goodpasture syndrome, a n autoimmune disease; Alport syndrome, a progressive hereditary form of glomerulonephritis; and
diffise leiomyomatosis, a hereditary disease characterized by benign proliferation of smooth muscle.
Recently, the molecular defects underlying Goodpasture and Alport syndromes as well as leiomyomatosis have been linked to type
IV collagen, a major structural component of BM. The major ubiquitous form of this protein isa heterotrimer containing al(IV) and
a2(IV) chains (2). Studies of the molecular pathology of BM have
led to thediscovery of four new chains (a3 to a6)
of type IV collagen
that have all
been'shown to be directly involved in thepathogenesis
of these diseases. In Goodpasture syndrome,the a3(IV) chainis the
Alport syndrome,
target for the pathogenic autoantibodies (3,4). In
the COL4A5 gene encoding the a5(IV) chain is mutated in the
common X-chromosome-linked form of thedisease (5, 61, and
COL4A3 and COUA4 genes are mutated in the rare autosomal
form. In leiomyomatosis, the COL4A5 and COL4A6 genes are deleted (7 ).
Type IV collagen may now be classified as a protein family of
triple helical isoforms consisting of six genetically distinct chains:
the classical al(1V) and a2(IV) chains and the newly discovered
a3(IV),a4(IV), a5(IV), and aG(1V) chains. The existence of the recentlyidentified chains raises numerous unanswered
questions
about their biological function, structure/function relationships,
gene organization and regulation, and involvement in diseases.
This minireview highlights the current knowledge and recent advances in the chemistry, biology, and pathology of type IV collagen.

* This minireview will be reprintedin the Minireview Compendium, which

will be available in December, 1993. Tjle original publications of our work
were supportedin part by National Inetltutes of Health Grant DK-18381and
by ants from the American Heart Assoclatlon and Speas Foundatlon (to
B. e"H.1, Howard Hughes Medical Institute (to S. T. R.), and Academy of
Finland, The Sigrid Juselius Foundation, and Finland's Cancer Institute (to

K. T.).

The abbreviationsused are: BM, basement membrane; GBM, glomerular

basement membrane;AS, Alport syndrome; DL, diffuse esophageal leiomyomatosis.

Structure and Supramolecular

Assembly of
v p e N Collagen
The building block (monomer) of the typeIV collagen network in
BM is a triple helical molecule composed of three a-chains (Fig. 1)
(1,2). Each chain is characterized
by a long collagenous domain of
-1400 residues of Gly-&a-Yaa repeats, which are interrupted at
several sites by short noncollagenous sequences, a -15-residue
noncollagenous amino terminus, and a-230-residue noncollagenous (NC1) domain at the carboxyl terminus. Each chain is extensively glycosylated, containing -50 hydroxylysine-linked disaccharide units along the collagenous domain and an asparaginelinked oligosaccharide unit located near the amino terminus (810). The complete sequences of the al(1V) and a2(IV) chains of
man, mouse, and Caenorhabditiselegans are known (11-16) as are
those of the al(1V) chain of Drosophila (17) and sea urchin (18),
a2(1V) chain of Ascaris suum (19), and the human a5W) chain
(20-22). About one-third of the sequences of the human and
bovine
a3(IV) and a4(IV) chains and the human a6(N) chain havealso
been reported(7,23-29). The chains are
highly homologous and fall
into two classes: an al-like classcomposed of al(IV), a3(IV), and
a5(IV) chains; andan a2-like class composed of a2(N), a4(IV), and
a6(IV) chains (7,28). The
existence of six a-chains allows for many
different kinds (isoforms) of triple helical monomer that differ in
type and stoichiometry of chains. However, little is known about
their actualcompositions (30). Evidence has been obtained forheterotrimers having chain
compositions of ( a l h a 2 and (&3)2a4(2,311
l ) ~(a3)3(4, 32).
and homotrimers of ( c ~ and
The triple helical monomers self-associate forminga suprastructure (Fig. 1).Several modes of interactions are known. Monomers
associate at the carboxyl termini (NC1-to-NC1) forming dimers and
at the amino termini forming tetramers. The carboxyl-terminal
associations are sometimes stabilized by interchain disulfide bonds
between NC1 domains (33).The short noncollagenous sequence a t
the amino terminus contains
4 cysteine residues that may participate in both intra- andintermolecular disulfide bonds (34). In addition to end-to-end interactions, triplehelical domains intertwine
and interact with
NC1 domains forming supercoiled structures (34,
35).The flexibility required for supercoiling is presumably provided
by the short noncollagenous interruptions in the triple helix. The
existence of several kinds of triple helical isoforms, differing in
chain composition, confers a diversity to the suprastructure in
which several different combinations of monomer-monomer interactions are possible, i.e. NC1-to-NC1, amino terminus to amino
terminus, helix-to-helix, and helix-to-NC1 interactions. The available evidence for NCI-NCI interactionsfavors association between
like kinds of monomers (36).
Discriminatory molecular interactions must operate during the
assembly of the suprastructure, including formation of triple helical monomers, end-to-end associations
of monomers, and supercoiling. The specificity for assembly of triple helical monomers (chain
selections) appearsto reside withinthe NC1domain of each
a-chain. The NC1 domain is a highly conserved structure that has
two homologous domains. The invariant residues, which include 12
cysteines in the form of six disulfide bonds, are presumed to be
essential for assembly of a generic monomer, and thevariable residues are presumed govern
to
the specificity of monomer association
(28, 37). The specificity for end-to-end associations at the carboxyl
terminus also appears to
reside within the NC1 domain and favors
association of like kinds of NC1 domains (36). The specificity for
end-to-endassociations at the amino terminus that
govern the
assembly of tetramers and supercoiling is unknown.
Tissue Distribution of a(N) Chains
The six a-chains differ considerably with respect to tissue distribution. The al(1V) and a2(IV) chains appear to be ubiquitous,
whereas the other chains have
a restricted distribution(38).Within
the kidney, the a3(IV) and a4(IV) chains have a similar distribution
and arelocalized to the GBM (39), as is thea5(IV) chain (20), while

26033

26034

Minireview: l)pe N Collagen

coL4A2-

Chromosome 13

COMA4 9 p COL4A3

::-s
1

10

1 ::::: : :

20

30

wH

Y
40

::: ::

+":
9'

51

FIG. 2. Schematic illustration

of the organizationand ctu0m-e
location of the mammalinn type N collagen g
e
n
aThe genes encoding
the six t
lV collagen chains are located paim+ in a head-tu-head fashion
on three%erent chromosomes. The genes
deswted b horizontal bars
(colored). For the C O W gene, the locataon of exom is &own by wrtical
bars and introm by a horizontal line. The ex0118 are numbered fromthe 6'
end of the gene. Intron sequences of unknownsize are indicated by cireles.

FIG.1.Schematic illustrationof the supr~tructureof type N collagen of rend GBM. Ibp panel,electron nucrogra h shows the GBM pcmtionedbetween the fenestrated capill
endothekun and the foot rocesses ofthe epithelium( p o d o g s ) . b f a y n e l , the building blockopthe
type
collagen network in
M is a trip e helicalmonomer. These selfassociate forming a suprastructure in which they associateat the carboxyl
termini forming dimers and at the amino termini forming tetramers. The
triple helical domainsintertwine and
interactwith the NC1 domains forming
su wiled structures. Lower panel, monomers are composedof
three
that are assembled fiumsix genetically distinctu-chaine (ul to 4 ,
%
*
a
forming several triple helical isoforms. These are exemlifiedby
the
(al~(q2)
h f o m , (a3h(u4) +form, and a hypothetical (a5?z(&) isoform.
The tnple h e l d domam 1s mkrrupted at several sites by short noncollagenw sequences (uertkal bars), which presumably confers flexibility. The
N-linked oligosaccharideCY-shapedcircles)is known for the (ul)z(u2)isofcirm
thetical forisoformscomposedof other chams. The electron
co
of b.s. moue, Department of b t o m y , MeGa
University, Monh%anada.

EE
%g
a
i

FIG.3. Schematic illustamtionof the ols(Iv) chain PII the targe4 autoantyen fpr Goodpasturr,autoantibodies The &odpa+me autoantibodies ind h e a d y to GBMof the renal glomerulus (photom
ph top)
Within GBM, the autoantibodies (shownin yellour)are
to the u3(W chain. This chain is assembled into a tri e hedmole+e
exemplified by the (u3)z(u4)hform. The epitop for t& autoanbbodiea MI
located within the 1x3NCl domain and is sublodized to the laat 36 amino
acid residues (opencircles) at the carboxyl +minus. The NC1 domaiqhss
two homologous subdomains, a feature that IS common to the NC1 &nnamof
six u(IV)the. The folding of the NC1
de6nedby the dx loops,
ph of the renal glomeru1s formed by SIX &sulfide bonds.The hght m
lus is courtesyof Dr.P.Killen, Departmentof P z l o g y , University of Michi-

+-

+main,

gan, Ann Arbor, MI.

tion of the newer chains presumably confersa specific BM funetion

of as yet unknown nature.

!&pe N Collagen Gene8

the al(W and a2(IV)chains are localized to the GBM, mesangial
The mammalian typeIV collagen genes havea unique arrangematrix, and v a d a r and tubular BMs (39). The a5(IV)chain is also
expressed in tissues other than kidney, but detailed immunohisto- ment in that they are located pairwisein a head-to-headfashion on
chemical studies have not been reported. The a3(W and a4(W three different chromosomes (Fig. 2) (7,4245). This implies that
through initial duplicationand inversion of
chains occur in BMs of synaptic muscle fibersbut not in extraayn- the genes have evolved
to al- and &-like genes.
aptic muscle fibers, endoneurial or perineurial nerve, or d
r
y
, an ancestral gene followed by divergence
whereas al(IV) and &(IV)chains occur in all these sites but in less The paired genes subsequently underwent two further rounds of
abundancein synaptic BM (40). The a3(IV)and a4(IV) chains occur duplication leading to the three closely opposed paire. The evoluin low abundance alongwith a l ( W and a2(IV)in lens capsule BM tion of type IV collagen genes has been Werent in lower orgagenes reside
(3)and aorta (41). The distributionof the aG(IV)chain has not been nisms, such as C. elegum, where the al(Wand
investigated at the protein level, but transcripts of the C O W 6 on Merent chromosomes (16).
The typeIV collagen genes appear to be large and complex, the
gene occur in a variety of tissues (7), the highest levelof expression
being observed in esophagus and lung. The tissue-specific diatribu-C O M l and C O W genes exceeding100kilobases containing62

Minireview: Q p e N Collagen

26035

and 51 exons, respectively (46, 73). Comparison of COL4Al and

C O W reveals considerable
homology between the genes withthe
majority of the exons having identical sizes. Similarly,
the genes for
the &-like chains share high structural homology (47, 48). The
C O W 1 and C O W genes,encoding the al(IV) and a2(IV)
chains, share a common 130-base pair promoter region (42") that
contains cis-acting elementsthat have uni- and bidirectional transcriptional activities(43,49). The properties of the promoters for
the two other gene pairs have not been elucidated,
but the distance
between the transcriptional initiation sites of C O W and
C O W 6 is 452 base pairs or less (7).

Role of 15pe IV CoZZagen in Diseases

Goodpasture Syndrome-This is a lethal form of autoimmune
disease that is characterizedby glomerulonephritisand pulmonary
hemorrhage, which are mediated by autoantibodies that are targeted to glomerular and alveolar BMs. Searches forthe identity of
the target BM component have culminatedin the discovery of the
a3(IV)and a4(IV) chains (3,4,27,28) and the identificationof the
a3(IV)chain as the primary target autoantigen (Fig.3) (4,361.This
identitywas established through extensive
studies of the molecular
and immunochemical properties of the soluble formof the antigen,
which was obtained by collagenase digestion of alveolar, glomerular, and lens BMs (3, 4, 27, 30, 36, 5&52). The existence of the
a3(IV) chain was recently verified by molecular cloning (23-261,
and its identity as the Goodpasture autoantigen was verified
on the
basis of autoantibody binding to recombinant NC1 domains (53).
Recent reports provide evidence for alternate splicing of a3(IV)
mRNA, suggesting that variants of the aS(IV) chain may be expressed in certain tissues (54,551,
The epitope for Goodpasture antibodies
has been localizedto the
carboxyl terminus of the NC1 domain of the a3(IV) chain, encompassing the last 36 residues, as the primary interactionsite (Fig. 3).
The evidence for this site includes a distinctive hydrophilic
amino
acid sequence, the identification of lysine and cystine as critical
residues, and the identi6cation of this region as critical for antibody bindingusing synthetic peptides(56). The epitopeis sequestered within the NC1-NC1 junction of two adjoining triple helical
monomers. Upondisruption of the conformation andlorquaternary
structure of this region by protein denaturants, the epitope is unmasked and becomes accessible for binding Goodpasture antibody
(57). Unmasking of the epitope by infection or organic solvents,
events which are thought to precede Goodpasture syndrome, may
play an important role in the etiology of the disease.
Alport Syndrome (M&This is a progressive hereditary kidney
disease characterized by hematuria, sensorineural hearing loss,
and ocular lesions with structural defects in glomerularBM (58).
The disease usually leads to terminal renal failure in males, while
females are mostly less severely affected. The genehquency has
been estimated to be 15000 (58). The disease is primarily X chromosome-linked, but autosomal forms have also
been reported. The
X-linked form has been associated with mutations in the C O W
gene encoding the a5(IV)collagen chain (5, 6, 59). More than 50
different mutations have now been identified in the C O W gene,
including single base mutations,large deletions, and other major
rearrangements such as inversions, insertions, and duplications
(6).A strikingfeature is that these mutations are dispersed in the
gene and no "hot spots"have thus far been identified. The
COL4A5
mutations, suchas those illustrated in Fig. 4, cause structural and
functional defectsin thetype IV collagen molecule and, therefore,
in theGBM network. For example, the large gene rearrangements
and splice mutations could result in complete loss of the a5(IV)
chain or they can cause gross struchanges in the protein
rendering it abnormally short or long. Also, glycine substitutionsin
the collagenous domain may
inhibit the formation of the triple helix
or destabilize it, analogous to the effects of corresponding mutations in type I collagen in osteogenesis imperfecta(60). The effects
of the numerous amino acid substitutions in theNC1 domain may
be more difficult to interpret. This highly conserved domain is
probably essential for correct alignmentof three u-chains prior to
helix formationand for the formation of intermolecularcross-links.
Any substitution of an evolutionarily conserved amino acid may,
therefore, affectthese functions and cause disease(61).
The extrarenal manifestationsin Alport syndrome suchas hear-

r1

Ran, rrprnl

.I

In,
FIG.

Br

4. Schematic illu&mtionof the consBQuBpcB8 of known

basemutationsin the COgene on the u

6
0collagen
%-a
irregular thickening and splitting of GBM, .which characterizes the omerular lesions ofAlport syndrome, are shown rn the electron micrograpf(top).

with Alprt syndrome are

The aMW chain and known mutations associated
illustrated by the horizonkrl bar (bottom).The black mgwm represent the
noncollagenous interruptions of the triple helix. The electron micro aph is
courte of D. W. Richardson, De artment of Pathology, University of%ansaa
MedicsCenter, Kansas City, K.8.

ing loss and ocular lesions canv a r ~

both
~ with respect to presence
and severity even within the same kindred. The reason for
this is
unclear, and at this time the phenotype generatedby a given mutation cannot be predicted. An interesting feature is that some
a5(IV)mutations are associated with the failure of stable incorporation and even absenceof the a3(IV) and a4(IV) chains into Alport
GBM (62-64). At present, the mechanism linking a mutation in
a5(IV) chain with failure to incorporate the a3(IV) and a4(IV)
chains is unknown. Mutations in a5(IV)chain may result in defective molecular assembly with subsequent proteolysis
of the a3(IV)
and a4(IV) chains or may result in defective synthesis through
some unknown effects on transcription or translation.
Autosomal inherited forms of Alport syndrome have been reported, although theyare much morerarethan the X-linked forms.
These cases also develop hematuria, end-stage renal failure, and
disrupted GBM structure. f i e b i n a r y studies indicated recessive
mutations in both COL4A3 and C O W 4 genes.2
Diffuse Esophageal Lewmyomatosis (Dw"Thisis a rare disease
characterized by beNgn smooth muscle cell proliferation that affects the esophagus as well as the female genital tract and tracheobronchial tree (65). This disease has also been associated with
Alport syndrome (65).In fact, 28 cases from14 families, which have
been documented, show cosegregationof DL and Alport syndrome
(66). Deletion of the 5' end of the COL4A5 gene has been reported
in three children with AS-DL (661, and deletions involving the 5'
end of COL4A5 extending into the second intron of the adjacent
C O W 6 gene were recently described in four patients with the
disease (7).Mutations involving onlyC O W or COL4A6 have, as
yet, not been found
in the disease. It is quite possible that, in some
cases, the a5(IV)and a6(IV) chains are not present in the same
triple helical molecule. This is supported by the observation of a
different lack of expression of the two genes in different tissues
such as esophagus and kidneys (7).

Conclusions and Perspectives

It is now well established that type IV collagen comprises a
of at least six genetically
family of triple helical isoforms consisting
distinct chains having a tissue-specific distribution. Withthe exception of the triple helical isoform comprised of the al(IV) and
a2(IV) chains, little is known about the chain composition of isoforms comprisedof the other chains, or their suprastructure. Also,
their tissue-specific functions, otherthan structural ones, are comS.T.Reeders, unpublisheddata.

Minireview: Tjtpe N Collagen

26036

pletely unknown. However, recent studies leading to the

discovery
of the minor a3(IV),a4(IV), a5(IV),and aG(IV)chains and demonstration of their involvement in the pathogenesis of Goodpasture
and Alport syndromes and leiomyomatosis have provided new insight into the structure and properties
of specialized BMs. The gene
mutations underlying Alport syndrome and leiomyomatosis, together with the limited tissue distribution of the corresponding
chains, clearly indicate specific biological functions for these
chains, including a vital role in the molecular sieve function of
GBM and in cell differentiation such as that of smooth muscle.
The recent advances in the chemistry, biology, and pathology of
type IV collagen have had andwill undoubtedly continue to havea
role
significant clinical impact. The stage now
is set to delineate the
of the six u(IV)collagen chains indiabetic renal disease and tumor
metastasis, as type IV collagen has been implicated in the pathogenesis of both (67-72). Knowledge of the pathogenic mechanism
underlying Goodpasture syndrome now provides the basis for development of new diagnostic tests and therapeuticprocedures. Exact diagnosis of Alport syndrome and hereditaryleiomyomatosis is
now possible, and theground is even ready for the development of
somatic gene therapy.
AcknowledgmentsSpace limitations preclude the acknowledgmentof all
of the original publications on
ty e IV collagen. We are deeply indebtedto our
graduate students, postdoctoraf fellows, technicians, a n d collaborators for
their contributionsto the work summarized here.
We thank Bill Paige for his
excellent artwork.

REFERENCES
1. Kefalides, N.A. (1971) Biochem. Biophys. Res. Commun. 46,226-234
2. ISmpl, R. (1989) Eur. J. Eimhem. 180,487502
3. Butkowski, R. J., Langeveld, J. P.M.. Wieslander, J., Hamilton, J., and Hudson, B. G . (1987) J. Biol. Chem. 262, 7874-7877
4. Saus, J., Wieslander, J., Langeveld, J. P. M., Quinones, S., and Hudson, B. G .
(1988) J . Biol. Chem. 263, 13374-13380
5. Barker, D. F., Hostikka, S. L., Zhou, J., Chow, L. T., Oliphant, A. R., Gerken, S.
C., Gregory, M. C., Skolnick, M. H., Atkin, C. L., and Tryggvason, K. (1990)
Science 248,1224-1227
6. Tryggvason, K., Zhou, J., Hostikka, S. L., and Shows, T. B. (1993) Kidney Int.
43,38-44
7. Zhou, J., Mochizuki, T., Smeets, H., Antignac, C., Laurila, L., de Paepe, A.,
Tryggvason, K , and Reeders, S. T. (1993)Science 261, 1167-1169
8. Spiro, R. G. (1967) J . Biol. Chem. 242, 1923-1932
9. Langeveld, J. l? M., Noelken, M. E., Hard, K., Todd, P., Vliegenthart, &use, J.,
and Hudson B. G . (1991) J. Biol. Chem. 266, 2622-2631
10. Nayak, B. R., and Spiro, R. G . (1991)J . Biol. Chem. 266, 1397a13987
11. Soininen, R.,Haka,R. T., Prockop, D. J., andTryggvason, K. (1987)FEBSLett.
225,188-194
12. Brazel, D., Oberbaumer, I., Dieringer, H., Babel, W., Glanville, R.W., Deutzmann, R., and Kuhn, K. (1987) Eur. J . Biochem. 168, 529-536
13. Hostikka, S. L., and Tryggvason, K. (1988) J . Biol. Chem. 263,1948%19493
14. Blumberg, B., MacKrell, A. J., Olson, P.F., Kurkinen, M., Monson, J. M.,
Natzle, J. E., and Fessler, J. H. (1987) J. Biol. Chem. 262, 5947-5950
15. Saus, J., Quinones, S., MacKrell, A., Blumberg, B., Muthukumaran, G.,Pihlajaniemi, T., and Kurkinen, M. (1989)J. Biol. Chem. 264,6318-6324
16. Guo, X.,and Kramer, J. M. (1989) J . Bid. Chem. 264, 17574-17582
17. Blumberg, B., MacKrell, A. J., and Fessler, J. H. (1988) J . Eiol. Chem. 283,
18328-18337
18. Exposito, J, Y., Alessio, M. D., Solursh, M., and Ramirez, F. (1992) J. Bid.
Chem. 267, 15559-15562
19. Pettitt, J., and Kingston, B. I. (1991) J . Biol. Chem. 266, 16149-16156
20. Hostikka, S. L.,Eddy, R. L., Byers, M. G., Hoyhtya, M., Shows, T.B., and
Ttyggvason, K. (1990) Proc. Natl. Acad. Sci. U. S. A. 87, 160S1610
21. Pihlajaniemi, T., Pohjolainen, E. R., and Myers, J. C. (199O)J.Biol. Chem. 265;
13758-13766
22. Zhou, J.,Hertz, J. M., Leinonen, A., and Tryggvason, K. (1992)J . Biol. Chem.
267, 12475-12481
23. Momson, K E., Germino, G . G., and Reeders, S. T. (1991) J. Biol. Chem. 266,
3439
24. Morrison, K. E., Mariyama, M.,Yang-Feng, T. L., and Reeders, S. T. (1991)Am.
J . Hum. Genet. 49,545-554
25. Turner. N.. Mason. P. J.. Brown. R.. Fox. M... Povev.
_ S..
, .Rees.. A.., and Pusev. C.
D.
J . C&n. IiAest. ss,asi-soi
26. Quinones, S., Bernal, D., Garcia-Sago, M., Elena, S. F., and Saus,J. (1992)J .
Bid. Chem. 267, 19780-19785
27. Gunwar, S., Saus, J., Noelken, M. E., and Hudson, B. G . (1990)J . Biol. Chem.
265.5466-5469
28. Mariyama, M., Kalluri, R., Hudson, B. G., and Reeders, S. (1992) J . Biol.
Chem. 267, 1253-1258
29. Sugimoto, M., Oohashi, T.,Yoshioka, H., Matsua, N., and Ninomiya, Y. (1993)
FEBS Lett. 330.122-128
30. Hudson, B. G., Wieslander, J., Wisdom, B. J., Jr., and Noelken, M. E. (1989)
Lab. Invest. 61,256-269
~~

31. Johansson, C., Butkowski, R., and Wieslander, J. (1992) J. Bid. Chem. 287,
24533-24537
32. Haralson, M. A., Federspeil, S. J., Martinez-Hernandez, A,, Rhodes, R. IL, and
Miller, E. J. (1985) Biochemistry 24,57924797
33. Timpl, R., Wiedemann, H., Van Veldon,V., Furthmayr, H., and Kuhn,K. (1981)
Eur. J. Biochem. 120,203-211
34. Siebold, B., Deutzmann, R., and Kuhn, K. (1988) Eur: J. Biochem. 176,617624
35. Yurchenko, P., and ORear, J. (1993) in Molecular and Cellular Aspects of
Basement Membranes (Rohrbach, D., and Timpl, R.. eda) pp. 19-47, h a demic Press, New York
36. Gunwar, s., Ballester, F., Kalluri, R., Timoneda, J., Chonko, A. M., Edwards, S.
J., Noelken. M. E., and Hudson, B. G. (1991) J. Biol. Chem. Zee, 1 5 3 1 a
15324
37. Dion, A. S., and Myers, J. C. (1987) J. Mol. Biol. 199, 127-143
38. Langeveld, J. P. M., Wieslander, J., Timoneda, J., McKinney, P.,Butkowski, R.
J., Wisdom, B. J., and Hudson, B. G . (1988) J. Biol. Chem. 265, 1048110488
39. Butkowski, R. J., Wieslander, J., Kleppel, M., Michael, A. F., and Fish, A. J.
(1989) Kidney Int. 36,1195-1202
40. Sanes, J. R., Engavall, E., Butkowski, R., and Hunter,D. D. (199O)J.Cell Bid.
111, 16%1
-699
41. Reddy, G . K., Gunwar, S., Kalluri, R., Hudson, B. G., and Noelken, M. E. (1993)
Biochim. Biophys. Acta 1167,241-251
42. Soininen, R., Huotari, M., Hostikka, S. L., Prockop, D. J., and Tryggvason, K.
(1988) J . Biol. Chem. 263, 17217-17220
43. Poschl, E., Pollner, R., and Kuhn, K (1988) EMBO J. 7, 2687-2695
44. Burbelo, P. D., Martin, G. R., and Yamada, Y. (1988) Proc. Natl. Aead. Sci.
U. S.A. 86,9679-9682
45. Mariyama, M., Zheng, K., Yang,T. T.L., and Reeders, S. T. (1992) Genomics 19,
8094313
46. Zhou, J., Leinonen, A., and Tryggvason, K (1994) J.Biol. Chem. m,in press
47. Hostikka, S. L., and Tryggvason, K. (1987) FEBS Lett. 224, 297405
48. Kamagata, Y., Mattei, M. G., and Ninomiya, Y. (1992) J. Biof. Chem. 267,
23753-23758
49. Heikkila, P., Soininen, R., and Tryggvason, K (1993) J. Biol. Chem. 268,
24677-24682
50. Dean, D. C., Barr, J. F., Freytag, J. W., and Hudson, B. G . (1983)J. Biol. Chem.
268,590-596
51. Wieslander, J., Barr, J. F., Butkowski, R. J., Edwards, S. J., Bygren, P., Heinegard, D.. and Hudson, B. G . (1984) Proc. Natl. Acad. Sei. U.S. A. 81,
3838-3842
52. Gunwar, S., Bejarano, P. A., Kalluri, R., Langeveld, J. P. M., Wlsdom, B.J., Jr.,
Noelken, M. E., and Hudson, B. G . (1991)Am. J. Respir. Cell Mol. Bwl. 6,
107-112
53. Neilson, E. G., Kalluri, R., Sun, M. J., Gunwar, S., Danloff, T., Mariyama, M.,
Myers, J. C., Reeders, S. T., and Hudson, B. G. (1993) J. Bid. Chem. 2
!68,
84024405
54. Bernal, D., Quinones, S., and Saus,J. (1993) J. Bid. Chem. 268,12090-12094
55. Feng, L., Xia, Y.,Tang, W.W., and Wilson, C. B. (1994) J . Biol. Chem. 2
!8
9
,in
press
56. Kalluri, R., Gunwar, S., Reeders, S. T.,Momson, K C., Mariyama, M., Ebner,
K. E., Noelken, M. E., and Hudson, B.G . (1991)J. Biol. Chem. Zsa,2401%
24024
57. Wieslander, J., Langeveld, J., Butkowski, R., Jodlowski, M., Noelken, M., and
Hudson, B. G. (1985) J . Bwl. Chem. 260,8564-8570
58. Atkins, C. L., Gregory,M. C., and Border, W. A. (1988) in Diseases of the Kidney
(Schrier, R. W., and Gottschalk, C. W., eds) pp. 617-641, Little, Brown and
Co., Boston
59. Zhou, J.. Barker, D.F., Hostikka, S. L., Gregory, M. C., Atkin, C . L., and
Tryggvason, K.(1991) Genomics 9,1&18
60. Prockop, D. J . (199O)J.Biol. Chem. 886, 15349-15352
61. Lemmink, H. H., Schriider, C. H., Brunner, H. G., Nelen, M. R., Zhou, J.,
Tryggvason, K, Haagsma-Schouten, W. A. G., Roodvoets,A. P., Rascher, W.,
van Oost, B. A,, and Smeets, H. J. M. (1993) Genomics 17,485-489
62. KleDoel. M. M.. Kasthan. C. E.. Butkowski., R. J.., Fish.. A. J..
. and Michael. A
$..(1987)J. Clin. Invest. 80,263-266
63. Hudson, B. G., Kalluri, R., Gunwar, S., Weber, M., Ballester, F., Hudson, J.,
Noelken. M. E.. Sarras. M., Richardson, W. R., Sam. J.. Abrahamson. D. R.,
Glick, A..D., Haralson, M. A,, Helderman, J. H., Stone,.W.J., andJacobson,
H. R. (1992)Kidnev Int. 42. 17S187
64. Kalluri, R., Weber, M , Netzer,K. O., Sun, M. E., Neilson, E. G., and Hudson,
B. G. (1994)Kidney Int., in press
65. Cochat, P., Guibaud, P., Garcia-Torres, P., Roussel, B., Guamer, V.,and Larbre,
F. (1988)J. Pediatr. 119,33=43
66. Antignac, C., Zhou, J., Sanak, M., Cochat, P., Roussel, B., Deschenes, G.,
Knebelmann, B., Hors, M. C., Tryggvason, K, and Gubler, M. C. (1992)
Kidney Znt. 42, 117&1183
67. Cohen, M.P., Urdanivia, E., Surma, M., and Wu, V.-Y. (1980) Biochem. Biophys. Res. Commun. 96,765-769
68. Spiro, R. G . (1988)in The Kidney and Hypertension in Diabetes (Mogensen, C .
E., ed) p. 117, Martinus Nijhoff, Boston
69. Tsilibary, E. C., Charonis, A. S., Reger, L. A., Wohlhueter, R. M., and Furcht, L.
T. (1988) J . Biol. Chem. 289,43024308
70. Kim, Y., Kleppel, M. M., Butkowski, R., Mauer, M. S., Wleslander, J., and
Michael, A.F. (1991) Am. J. Pathol. 138,413420
71. Doi, T., Vlassara, H., Kirstein, M., Yamada, Y., Striker, 0.E., and Striker,L.J.
(1992)Proc. Natl. Acad. Sci. U. S. A. 89,2873-2877
72. Aznavmrian, S., Murthy, A. N., Strtler-Stevenson. W.G., and Liotta, L. A.
(1993) Cancer 71,1368-1383
73. Soininen, R., Huotari, M., Ganguly, A, Pmckop, D. J., and Tryggvamn, K.
(1989)J . Biol. Chem. 264,13565-13571