Abstract
Both thin basement membrane nephropathy (TBMN) and autosomal recessive Alport syndrome result from mutations in the COL4A3 and COL4A4 genes, and this study documents further mutations and polymorphisms in these genes.
Thirteen unrelated children with TBMN and five individuals with autosomal recessive Alport syndrome were examined for mutations in the 52 exons of COL4A3 and the 47 coding exons of COL4A4 using single-stranded conformation polymorphism (SSCP) analysis. Amplicons producing different electrophoretic patterns were sequenced, and mutations were defined as variants that changed an amino acid but were not present in 50 non-hematuric normals.
Three further novel mutations were identified. These were IVS 22-5 T>A in the COL4A3 gene in a consanguineous family with autosomal recessive Alport syndrome, and R1677C and R1682Q in the COL4A4 gene. In addition, six novel polymorphisms (G455G, I462I, G736G and IVS 38-8 G>A in COL4A3, and L658L and A1577A in COL4A4) were demonstrated.
Many different COL4A3 and COL4A4 mutations cause TBMN and autosomal recessive Alport syndrome. The identification of polymorphisms in these genes is particularly important to enable diagnostic laboratories to distinguish mutations from uncommon normal variants.
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Abbreviations
- SSCP:
-
single stranded conformational polymorphism
- ESE:
-
exon splicing enhancer
- GBM:
-
glomerular basement membrane
- TBMN:
-
thin basement membrane nephropathy
References
Levy M, Feingold J (2000) Estimating prevalence in single-gene kidney diseases progressing to renal failure. Kidney Int 58:925–943
Feingold J, Bois E, Chompret A, Broyer M, Gubler M-C, Grunfeld J-P (1985) Genetic heterogeneity of Alport syndrome. Kidney Int 27:672–677
Barker DF, Hostikka SL, Zhou 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
Mochizuki T, Lemmink HH, Mariyama M, Antignac C, Gubler MC, Pirson Y, Verellen-Dumoulin C, Chan B, Schroder CH, Smeets HJ, Reeders ST (1994) Identification of mutations in the alpha 3(IV) and alpha 4(IV) collagen genes in autosomal recessive Alport syndrome. Nat Genet 8:77–81
Lemmink HH, Mochizuki T, van den Heuvel LP, Schroder CH, Barrientos A, Monnens LA, van Oost BA, Brunner HG, Reeders ST, Smeets HJ (1994) Mutations in the type IV collagen alpha 3 (COL4A3) gene in autosomal recessive Alport syndrome. Hum Mol Genet 3:1269–1273
Jefferson JA, Lemmink HH, Hughes AE, Hill CM, Smeets HJ, Doherty CC, Maxwell AP (1997) Autosomal dominant Alport syndrome linked to the type IV collagen a3 and a4 genes (COL4A3 and COL4A4). Nephrol Dial Transplant 12:1595–1599
Savige J, Rana K, Tonna S, Buzza M, Dagher H, Wang YY (2003) Thin basement membrane nephropathy. Kidney Int 64:1169–1178
Tryggvason K, Patrakka J (2006) Thin basement membrane nephropathy. J Am Soc Nephrol 17:813–822
Buzza M, Wilson D, Savige J (2001) Segregation of hematuria in thin basement membrane disease with haplotypes at the loci for Alport syndrome. Kidney Int 59:1670–1676
Buzza M, Wang YY, Dagher H, Babon JJ, Cotton RG, Dowling J, Savige J (2001) Identification of a COL4A4 mutation in thin basement membrane disease (TBMD) previously described in autosomal recessive Alport syndrome. Kidney Int 60:480–483
Ozen S, Ertoy D, Heidet L, Cohen-Solal L, Ozen H, Besbas N, Bakkaoglu A, Antignac C (2001) Benign familial hematuria associated with a novel COL4A4 mutation. Pediatr Nephrol 16:874–877
Badenas C, Praga M, Tazon B, Heidet L, Arrondel C, Armengol A, Andres A, Morales E, Camacho JA, Lens X, Davila S, Mila M, Antignac C, Darnell A, Torra R (2002) Mutations in the COL4A3 and COL4A4 genes cause familial benign hematuria. J Am Soc Nephrol 13:1248–1254
Longo I, Porcedda P, Mari F, Giachino D, Meloni I, Deplano C, Brusco A, Bosio M, Massella L, Lavoratti G, Roccatello D, Frasca G, Mazzucco G, Muda AO, Conti M, Fasciolo F, Arrondel C, Heidet L, Renieri A, De Marchi M (2002) COL4A3/COL4A4 mutations: from familial hematuria to autosomal-dominant or recessive Alport syndrome. Kidney Int 61:1947–1956
Buzza M, Dagher H, Wang YY, Wilson D, Babon JJ, Cotton RG, Savige J (2003) Mutations in the COL4A4 gene in thin basement membrane disease. Kidney Int 63:447–453
Tazon-Vega B, Badenas C, Ars E, Lens X, Mila M, Darnell A, Torra R (2003) Autosomal recessive Alport’s syndrome and benign familial hematuria are collagen type IV diseases. Am J Kidney Dis 42:952–959
Gross O, Netzer KO, Lambrecht R, Seibold S, Weber M (2003) Novel COL4A4 splice defect and in-frame deletion in a large consanguine family as a genetic link between benign familial haematuria and autosomal Alport syndrome. Nephrol Dial Transplant 18:1122–1127
Wang YY, Rana K, Tonna S, Lin T, Sin L, Savige J (2004) COL4A3 mutations and their clinical consequences in thin basement membrane nephropathy (TBMN). Kidney Int 65:786–790
Fairley KF, Birch DF (1982) A simple method for identifying glomerular bleeding. Kidney Int 21:105–108
Rana K, Wang YY, Powell H, Jones C, McCredie D, Buzza M, Udawela M, Savige J (2005) Persistent hematuria in children and the thin basement membrane nephropathy (TBMN) locus at COL4A3/COL4A4. Pediatr Nephrol 20:1729–1737
Dagher H, Wang YY, Fassett R, Savige J (2002) Three novel COL4A4 mutations resulting in stop codons and their clinical effects in autosomal recessive Alport syndrome. Hum Mutat 20:321–322
Boye E, Mollet G, Forestier L, Cohen-Solal L, Heidet L, Cochat P, Grunfeld JP, Palcoux JB, Gubler MC, Antignac C (1998) Determination of the genomic structure of the COL4A4 gene and of novel mutations causing autosomal recessive Alport syndrome. Am J Hum Genet 63:1329–1340
Heidet L, Arrondel C, Forestier L, Cohen-Solal L, Mollet G, Guttierez B, Stavrou C, Gubler M-C, Antignac C (2001) Structure of the human type IV collagen gene COL4A3 and mutations in autosomal Alport syndrome. J Am Soc Nephrol 12:97–106
Orita M, Iwahana H, Kanazawa H, Hayashi K, Sekiya T (1989) Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc Natl Acad Sci USA 86:2766–2770
Fairbrother WG, Yeo GW, Yeh R, Goldstein P, Mawson M, Sharp PA, Burge CB (2004) RESCUE-ESE identifies candidate exonic splicing enhancers in vertebrate exons. Nucleic Acids Res 32:W187–W190
van der Loop FT, Heidet L, Timmer ED, van den Bosch BJ, Leinonen A, Antignac C, Jefferson JA, Maxwell AP, Monnens LA, Schroder CH, Smeets HJ (2000) Autosomal dominant Alport syndrome caused by a COL4A3 splice site mutation. Kidney Int 58:1870–1975
Ciccarese M, Casu D, Wong KF, Faedda R, Arvidsson S, Tonolo G, Luthman H, Satta A (2001) Identification of a new mutation in the alpha 4(IV) collagen gene in a family with autosomal dominant Alport syndrome and hypercholesterolemia. Nephrol Dial Transplant 16:2008–2012
Pescucci C, Mari F, Longo L, Vogiatzi P, Caselli R, Scala E, Abaterusso C, Gusmano R, Seri M, Miglietti N, Bresin E, Renieri A (2004) Autosomal-dominant Alport syndrome: natural history of a disease due to COL4A3 or COL4A4 gene. Kidney Int 65:1598–1603
Perry GJ, George CR, Field MJ, Collett PV, Kalowski S, Wyndham RN, Newland RC, Lin BP, Kneale KL, Lawrence JR (1989) Thin-membrane nephropathy—a common cause of glomerular haematuria. Med J Aust 151:638–642
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This work was supported by the National Health and Medical Research Council of Australia.
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Rana, K., Tonna, S., Wang, Y.Y. et al. Nine novel COL4A3 and COL4A4 mutations and polymorphisms identified in inherited membrane diseases. Pediatr Nephrol 22, 652–657 (2007). https://doi.org/10.1007/s00467-006-0393-y
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DOI: https://doi.org/10.1007/s00467-006-0393-y