Abstract
Alport syndrome (AS) is an hereditary disease of basement membranes characterized by progressive renal failure and deafness. Changes in the glomerular basement membrane (GBM) in AS suggest that the type IV collagen matrix, the major structural component of GBM, is disrupted. We recently isolated the genes for two type IV collagens, α3(IV) and α4(IV), that are encoded head-to-head on human chromosome 2. These chains are abundant in normal GBM but are sometimes absent in AS. We screened for mutations in families in which consanguinity suggested autosomal recessive inheritance. Homozygous mutations were found in α3(IV) in two families and in α4(IV) in two others, demonstrating that these chains are important in the structural integrity of the GBM and that there is an autosomal form of AS in addition to the previously-defined X-linked form.
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References
Atkin, C.L., Gregory, M.C. & Border, W.A., Alport Syndrome. in Diseases of the Kidney 4th edn (eds Schrier, R.W. & Gottschalk, C.W.) 1, 617–641 (Little, Brown and Company, Boston, 1988).
Hudson, B.G., Reeders, S.T. & Tryggvason, K. Type IV collagen: structure, gene organization, and role in human diseases. J. biol. Chem. 288, 26033–26036 (1993).
Hostikka, S.L. & Tryggvason, K. The complete primary structure of the α2 chain of human type IV collagen and comparison with the α1(IV) chain. J. biol. Chem. 263, 19488–19493 (1988).
Butkowski, R.J., Langeveld, J.P., Wieslander, J., Hamilton, J. & Hudson, B.G. Localization of the Goodpasture epitope to a novel chain of basement membrane collagen. J. biol. Chem. 262, 7874–7877 (1987).
Saus, J., Wieslander, J., Langeveld, J.P., Quinones, S. & Hudson, B.G. Identification of the Goodpasture antigen as the α3(lV) chain of collagen IV. J. biol. Chem. 263, 13374–13380 (1988).
Morrison, K.E., Germino, G.G. & Reeders, S.T. Use of the polymerase chain reaction to clone and sequence a cDNA encoding the bovine α3 chain of type IV collagen. J. biol. Chem. 266, 34–39 (1991).
Gunwar, S., Saus, J., Noelken, M.E. & Hudson, B.G. Glomerular basement membrane. Identification of a fourth chain, α4, of type IV collagen. J. biol. Chem. 265, 5466–5469 (1990).
Mariyama, M., Kalluri, R., Hudson, B.G. & Reeders, S.T. The α4(IV) chain of basement membrane collagen. Isolation of cDNAs encoding bovine α4(IV) and comparison with other type IV cllagens. J. biol. Chem. 287, 1253–1258 (1992).
Hostikka, S.L. et al. Identification of a distinct type IV collagen α chain with restricted kidney distribution and assignment of its gene to the locus of X chromosome-linked Alport syndrome. Proc. natn. Acad. Sci. U.S.A. 87, 1606–1610 (1990).
Pihlajaniemi, T., Pohjolainen, E.R. & Myers, J.C. Complete primary structure of the triple-helical region and the carboxyl-terminal domain of a new type IV collagen chain, α5(lV). J. biol. Chem. 265, 13758–13766 (1990).
Zhou, J. et al. Deletion of the paired α5(IV) and α6(IV) collagen genes in inherited smooth muscle tumors. Science 261, 1167–1169 (1993).
Timpl, R. Structure and biological activity of basement membrane proteins. Eur. J. Biochem. 180, 487–502 (1989).
Hudson, B.G., Wieslander, J., Wisdom, B.J. Jr. & Noelken, M.E. Goodpasture syndrome: molecular architecture and function of basement membrane antigen. Lab. Invest. 61, 256–269 (1989).
Kleppel, M.M., Santi, P.A., Cameron, J.D., Wieslander, J. & Michael, A.F. Human tissue distribution of novel basement membrane collagen. Am. J. Pathol. 134, 813–825 (1989).
Butkowski, R.J., Wieslander, J., Kleppel, M., Michael, A.F. & Fish, A.J. Basement membrane collagen in the kidney: regional localization of novel chains related to collagen IV. Kidney Int. 35, 1195–1202 (1989).
Sanes, J.R., Engvall, E., Butkowski, R. & Hunter, D.D. Molecular heterogeneity of basal laminae: isoforms of laminin and collagen IV at the neuromuscular Junction and elsewhere. J. cell Biol. 111, 1685–1699 (1990).
McKusick, V.A. Mendelian inheritance in man 10th edn (Johns Hopkins University Press, Baltimore, 1992).
Barker, D.F. et al. Identification of mutations in the COL4A5 collagen gene in Alport syndrome. Science 248, 1224–1227 (1990).
Tryggvason, K., Zhou, J., Hostikka, S.L. & Shows, T.B. Molecular genetics of Alport syndrome. Kidney Int. 43, 38–44 (1993).
Feingold, J. et al. Genetic heterogeneity of Alport syndrome. Kidney Int. 27, 672–677 (1985).
Passwell, J.H., David, R., Boichis, H. & Herzfeld, S. Hereditary nephritis with associated defects in proximal renal tubular function. J. Pediatr. 98, 85–87 (1981).
Habib, R. et al. Alport's syndrome: experience at Hôpital Necker. Kidney Int. 11, 320–828 (1982).
Kleppel, M.M., Kashtan, C.E., Butkowski, R.J., Fish, A.J. & Michael, A.F. Alport familial nephritis. Absence of 28 kilodalton non-collagenous monomers of type IV collagen in glomerular basement membrane. J. clin. Invest. 80, 263–266 (1987).
Olson, D.L. et al Diagnosis of hereditary nephritis by failure of glomeruli to bind anti-glomerular basement membrane antibodies. J. Pediatr. 96, 697–699 (1980).
Kleppel, M.M., Fan, W.W., Cheong, H.I., Kashtan, C.E. & Michael, A.F. Immunochemical studies of the Alport antigen. Kidney Int. 41, 1629–1637 (1992).
Morrison, K.E., Mariyama, M., Yang-Feng, T.L. & Reeders, S.T. Sequence and localization of a partial cDNA encoding the human alpha 3 chain of type IV collagen. Am. J. hum. Genet. 49, 545–554 (1991).
Mariyama, M., Zheng, K., Yang-Feng, T.L. & Reeders, S.T. Colocalization of the genes for the α3(IV) and α4(IV) chains of type IV collagen to chromosome 2 bands q35–q37. Genomics 13, 809–813 (1992).
V.d.Heuvel, L.P. et al. The development of anti-glomerular basement membrane nephritis in two children with Alport"s syndrome after renal transplantation: characterization of the antibody target. Pediatric Nephrology 3, 406–413 (1989).
Turner, N. et al. Molecular cloning of the human Goodpasture antigen demonstrates it to be the α3 chain of type IV collagen. J. clin. Invest. 89, 592–601 (1992).
Hudson, B.G. et al. Molecular characteristics of the Goodpasture autoantigen. Kidney Int. 43, 135–139 (1993).
Quinones, S., Bernal, D., Garcia-Sogo, M., Elena, S.F. & Saus, J. Exon/intron structure of the human α3(IV) gene encompassing the Goodpasture antigen (α3(IV)NC1). Identification of a potentially antigenic region at the triple helix/ NC1 domain junction. J. biol. Chem. 267, 19780–19784 (1992).
Reeders, S.T. Molecular genetics of hereditary nephritis. Kidney Int. 42, 783–792 (1992).
Kulvaniemi, H., Tromp, G. & Prockop, D.J. Mutations in collagen genes: causes of rare and some common diseases in humans. FASEB J. 5, 2052–2060 (1991).
Marini, J.C., Lewis, M.B., Wang, Q., Chen, K.J. & Orrison, B.M. Serine for glycine substitutions in type I collagen in two cases of type IV osteogenesis imperfecta(OI). Additional evidence for a regional model of OI pathophysiology. J. biol. Chem. 268, 2667–2673 (1993).
Kamagata, Y., Mattei, M.G. & Ninomiya, Y. Isolation and sequencing of cDNAs and genomic DNAs encoding the α4 chain of basement membrane collagen type IV and assignment of the gene to the distal long arm of human chromosome 2. J. biol. Chem. 267, 23753–23758 (1992).
Sugimoto, M., Oohashi, T., Yoshioka, H., Matsuo, N. & Ninomiya, Y. cDNA isolation and partial gene structure of the human α4(IV) collagen chain. FEBS Lett. 330, 122–128 (1993).
Johansson, C., Butkowski, R. & Wieslander, J. The structural organization of type IV collagen. Identification of three NC1 populations in the glomerular basement membrane. J. biol. Chem. 267, 24533–24537 (1992).
Renieri, A. et al. Abstract. Am. J. hum. Genet. 53, Suppl. 1219A (1993).
Chirgwin, J.M., Przybyla, A.E., MacDonald, R.J. & Rulter, W.J. Isolation of biologically active ribonucleic acids from sources enriched in ribonuclease. Biochemistry 18, 5294–5299 (1979).
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Mochizuki, T., Lemmink, H., Mariyama, M. et al. Identification of mutations in the α3(IV) and α4(IV) collagen genes in autosomal recessive Alport syndrome. Nat Genet 8, 77–82 (1994). https://doi.org/10.1038/ng0994-77
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DOI: https://doi.org/10.1038/ng0994-77
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