Autosomal dominant Alport syndrome caused by a COL4A3 splice site mutation

Background Alport syndrome (AS) is a clinically and genetically heterogeneo us renal disorder, predominantly affecting the type IV collagen alpha3/alph a4/alpha5 network of the glomerular basement membrane (GBM). AS can be caus ed by mutations in any of the three genes encoding these type IV collagen c hains. The majority of AS families (85%) are X-linked (XL-AS) involving mut ations in the COL4A5 gene. Mutations in the COL4A3 and COL4A4 genes cause a utosomal recessive AS (AR-AS), accounting for approximately 14% of the case s. Recently, autosomal dominant AS (AD-AS) was linked to the COL4A3/COL4A4 locus in a large family. Methods. COL4A3 and COL4A4 cDNAs were generated by nested reverse transcrip tion-polymerase chain reaction and were analyzed by DNA sequence analysis. Denaturating highperformance liquid chromatography (DHPLC) was used for mut ation and segregation analysis at the genomic DNA level. Results. In the AD-AS family, a splice site mutation resulting in skipping of exon 21 of the COL4A3 gene was detected. The mutation does not alter the reading frame and is predicted to result in a COL4A3 chain with an interna l deletion. Conclusion. As the NC domain is intact, this chain may be incorporated and distort the collagen triple helix, thereby causing the dominant effect of t he mutation. The finding of a specific COL4A3 mutation in AD-AS completes t he spectrum of type IV collagen mutations in all genetic forms of AS.