Abstract
Thirty one families with Alport syndrome including 3 families with associated syndromes were studied. The location of the COL4A5 gene, responsible for the Alport syndrome, was determined by linkage analysis with eight probes of the Xq arm and by a radiation hybrid panel. Concordant data indicated the localization of the Alport gene between DXS17 and DXS11. Four deletions and one single base mutation of the COL4A5 gene were detected. Homogeneity tests failed to show any evidence of genetic heterogeneity superimposed on clinical heterogeneity for ophthalmic signs and end-stage renal disease age.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Aldridge J, Kunkel L, Bruns G, Tantravahi U, Lalond M, Brewster T, Moreau E, Wilson M, Bromley W, Roderick T, Latt SA (1984) A strategy to reveal high-frequency RFLPs along the human X chromosome. Am J Hum Genet 36:546–564
Antignac C, Zhou J, Sanak M, Cochat P, Roussel B, Desehenes G, Gros F, Knebelman B, Hors-Cayla MC, Tryggvason K, Gubler MC (1992) Alport syndrome associated with diffuse oesophagal leiomyomatosis: deletions at the 5′ end and upstream region of the COL4A5 collagen gene. Kidney Int 42:1178–1183
Atkin CL, Hasstedt SJ, Menlove L, Cannon L, Kirschner N, Schwartz C, Nguyen K, Skolnick MH (1988) Mapping of Alport syndrome to the long arm of the X chromosome. Am J Hum Genet 42:249–255
Barker D, Hostikka SL, Shou J, Chow LT, Oliphant AR, Gerken SC, Gregory MC, Skolnick MH, Atkin CL, Tryggvason K (1990) Identification of mutations in the COL4A5 collagen gene in Alport syndrome. Science 248:1224–1227
Barker D, Fain P, Goldgar D, Dietz-Band J, Turco A, Kashtan C, Gregory M, Tryggvason K, Skolnick M, Atkin C (1991) High density genetic and physical mapping of DNA markers near X-linked Alport syndrome locus: definition and use of flanking polymorphic markers. Hum Genet 88:189–194
Boye D, Vetrie D, Flinter F, Buckle B, Pihlajaniemi T, Hamalainen ER, Myers J, Bobrow M, Harris A (1991) Major rearrangements in the alpha5(IV) collagen gene in three patients with Alport syndrome. Genomics 11:1125–1132
Brunner H, Schroder C, Bennekom C van, Lambermon E, Tuerling J, Menzel D, Olbing H, Monnens L, Wieringa B, Ropers H-H (1988) Localization of the gene for X-linked Alport's syndrome. Kidney Int 34:507–510
Clarke A, Safarazi M, Thomas NST, Roberts K, Harper S (1987) X-linked hypohydrotic ectodermal dysplasia: DNA probe linkage analysis and gene localization. Hum Genet 75:378–380
Cochat P, Guibaud P, Garcia Torres R, Roussel B, Guarner V, Larbre F (1988) Diffuse leiomyomatosis in Alport syndrome. J Pediatr 113:339–343
Coneally PM, Edwards JH, Kidd KK, Lalouel JM, Morton NE, Ott J, White R (1985) Report of the committee on methods of linkage analysis and reporting. (8th International Workshop on Human Gene Mapping) Cytogenet Cell Genet 40:356–359
Cooke H, Bhattacharya SS, Fantes JA, Green DK, Evans HJ (1985) Preparation of X-chromosome specific probes from a flow sorted library. Cytogenet Cell Genet 40:607
Cox DR, Pritchard CA, Uglum E, Casher D, Kobori J, Myers RM (1989) Segregation of the Huntington disease region of human chromosome 4 in a somatic cell hybrid. Genomics 4:397–407
Cox DR, Burmeister M, Roydon Price E, Suwon Kim, Myers RM (1990) Radiation hybrid mapping: a somatic cell genetic method for constructing high-resolution maps of mammalian chromosomes. Science 250:245–250
Cremers FPM, Pfeiffer RA, Van de Pol TJR, Hofker MH, Kruse TA, Wieringa B, Ropers HH (1987) An interstitial duplication of the X chromosome in a male allows physical fine mapping of probes from the Xq13-Xq22 region. Hum Genet 77:23–27
Davies KE, Mandel J-L, Monaco AP, Nussbaum RL, Willard HF (1991) Committee on the genetic constitution of the X chromosome, 11th International Workshop on Human Gene Mapping Cytogenet Cell Genet 58:853–966
Drayna D, Davies KE, Hartley DA, Mandel JL, Camerino G, Williamson R, White RL (1984) Genetic mapping of the X chromosome by using RFLPs. Proc Natl Acad Sci USA 81:2836–2839
Epstein CJ, Sahud MA, Piel CF, Goodman JR, Bernfield MR, Kushner JH, Abiin AR (1972) Hereditary macrothrombocytopathia, nephritis and deafness. Am J Med 52:299–310
Feingold J, Bois E (1987) Genetics of Alport's syndrome. Pediatr Nephrol 1:436–438
Flinter AF, Abbs S, Bobrow M (1989) Localization of the gene for classic Alport syndrome. Genomics 4:335–338
Francke U, Ochs HD, Martinville B de, Giacalone J, Lindgren V, Disteche C, Pagon RA, Hofker MH, Ommen GJB van, Pearson PL, Wedgwood RJ (1985) Minor Xp21 chromosome deletion in a male associated with expression of Duchenne muscular dystrophy, chronic granulomatous disease, retinitis pigmentosa and McLeod syndrome. Am J Hum Genet 37:250–267
Garcia-Torres R, Guarner V (1983) Leiomiomatosis del esofago, traqueo bronquial y genital asociada con nefropatia hereditaria tipo Alport: un nuevo sindrome. Rev Gastroenterol Mex 70:163–170
Goodfellow PN, Davies KE, Ropers HH (1985) Report of the committee on genetic constitution of the X and Y chromosomes. (8th International Workshop on Human Gene. Mapping) Cytogenet Cell Genet 40:296–352
Habib R, Gubler MC, Hinglais N, Noel LH, Droz D, Levy M, Mahieu P, Foidart JM, Perrin D, Bois E, Grunfeld JP (1982) Alport's syndrome: experience at Hôpital Necker. Kidney Int 21 [Suppl 11]:20–28
Hasstedt SJ, Atkin CL, San Juan AC (1986) Genetic heterogeneity among kindreds with Alport syndrome. Am J Hum Genet 38:940–953
Hertz JM, Kruse TA, Thomsen A, Spencer ES (1991) Alport syndrome:linkage to nine X-chromosomal RFLP markers in fourteen Danish families. Am J Hum Genet [Suppl] 4:343
Hostikka SL, Eddy RL, Byers MG, Hoyhtya M, Shows TB, Tryggvason K (1990) Identification of a distinct type IV collagen alpha chain with restricted kidney distribution and assignment of its gene to the locus of X chromosome-linked Alport syndrome. Proc Natl Acad Sci USA 87:1606–1610
Kashtan CE, Michael AF (1989) Hereditary nephritis. Semin Nephrol 9:135–146
Knebelman B, Deschenes G, Gros F, Hors-Cayla MC, Grunfeld JP, Zhou J, Tryggvason K, Gubler MC, Antignac C (1992) Substitution of arginine for glycine 325 in the collagen alphaS (IV) chain associated with X-linked Alport syndrome: characterisation of the mutation by direct sequencing of PCR-amplified lymphoblast cDNA fragments. Am J Hum Genet 51:135–142
Lathrop GM, Lalouel JM, Julier C, Ott J (1984) Strategies for multilocus linkage analysis in humans. Proc Natl Acad Sci USA 81:3443–3446
Mariyama M, Kalluri R, Hudson BG, Reeders ST (1992) The alpha4(IV) chain of basement membrane collagen — isolation of cDNA encoding bovine alpha4(IV) and comparision with other type-IV collagens. J Biol Chem 267:1253–1258
McKusick VA (1990) Mendelian inheritance in man, 9th edn. Johns Hopkins University Press, Baltimore, p 592
Miyoshi K, Suzuki M, Ohno F, Yamano T, Yagi F, Khono H (1975) Antithyroid antibodies in Alport's syndrome. Lancet 11:480–482
Morrison KE, Germino GC, Reeders S (1991) Use of the polymerase chain reaction to clone and sequence a cDNA encoding the bovine alpha3 chain of type IV collagen. J Biol Chem 266:34–39
Morton NE (1956) The detection and estimation of linkage between the genes for elliptocytosis and the Rh blood type. Am J Hum Genet 8:80–96
Ott J (1985) Analysis of human genetic linkage. Johns Hopkins University Press, Baltimore
Passwell JH, David R, Boichis H, Herzfeld S (1981) Hereditarynephritis with associated defects in proximal renal tubular function. J Pediatr 98:85–87
Peterson LC, Rao V, Crosson JT, White G (1985) Fechtner syndrome. A variant of Alport's syndrome with leucocyte inclusions and macrothrombocytopenia. Blood 65:397–406
Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning: a laboratory manual. 2nd edn. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY
Schmeckpeper BJ, Davis J, Willard HF, Smith KD (1985) An anonymous single-copy X-chromosome RFLP for DXS72 from Xq14-Xq22. Nucleic Acids Res 13:5724
Smeets H, Melenhorst JJ, Lemmink HH, Schroeder CH, Nelen MR, Zhou J, Hostikka SL, Tryggvason K, Ropers HH, Jansweijer CE, Monnens LAH, Brunner HG, Ost BA van (1992) Mutations in the COL4A5 collagen gene leading to different types of Alport syndrome. Kidney Int 42:83–88
Smith CAB (1963) Testing for heterogeneity of recombination values in human genetics. Am J Hum Genet 27:175–182
Szpiro-Tapia S, Bobrie G, Guilloud-Bataille M, Heuertz S, Julier C, Frézal J, Grunfeld JP, Hors-Cayla MC (1988) Linkage studies in X-linked Alport's syndrome. Hum Genet 81:85–87
Zhou J, Hostikka SL, Chow LT, Tryggvason K (1991a) Characterization of the 3′half of the human type IV collagen alpha5 gene that is affected in the Alport syndrome. Genomics 9:1–9
Zhou J, Barker DF, Hostikka SL, Gregory MC, Atkin CL, Tryggvason K (1991b) Single base mutation in alpha5(IV) collagen chain gene converting a conserved cysteine to serine in Alport syndrome Genomics 9:10–18
Zhou J, Hertz JM, Tryggvason K (1992a) Mutation in the alphaS (IV) collagen chain in juvenile onset Alport syndrome without hearing loss or ocular leasions. Detection by DGGE of a PCR-product. Am J Hum Genet 50:1291–1300
Zhou J, Hertz JM, Leinonen A, Tryggvason K (1992b) Complete amino acid sequence of the human alpha5(IV) collagen chain and identification of a single base mutation in exon 29 from the 3′ end converting glycine-521 in the collagenous domain to cysteine in an Alport syndrome patient. J Biol Chem 267:12475–12481
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
M'Rad, R., Sanak, M., Deschenes, G. et al. Alport syndrome: a genetic study of 31 families. Hum Genet 90, 420–426 (1992). https://doi.org/10.1007/BF00220471
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00220471