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Background  Alport syndrome is an inherited renal disorder characterized by glomerular basement membrane lesions with hematuria, proteinuria and frequent hearing defects and ocular abnormalities. The disease is associated with mutations in genes encoding α3, α4, or α5 chains of type IV collagen, namely  COL4A3  and  COL4A4  in chromosome 2 and  COL4A5  in chromosome X. In contrast to the well-known X-linked and autosomal recessive phenotypes, there is very little information about the autosomal dominant. In view of the wide spectrum of phenotypes, an exact diagnosis is sometimes difficult to achieve.    Methods  We investigated a Spanish family with variable phenotype of autosomal dominant Alport syndrome using clinical, histological, and genetic analysis.    Results  Mutational analysis of  COL4A3  and  COL4A4  genes showed a novel heterozygous mutation (c. 998G > A; p.G333E) in exon 18 of the  COL4A3  gene. Among relatives carrying the novel mutation, the clinical phenotype was variable. Two additional  COL4A3  mutations were found, a Pro-Leu substitution in exon 48 (p.P1461L) and a Ser-Cys substitution in exon 49 (p.S1492C), non-pathogenics alone.    Conclusion  Carriers of p.G333E and p.P1461L or p.S1492C mutations in COL4A3 gene appear to be more severely affected than carriers of only p.G333E mutation, and the clinical findings has an earlier onset. In this way, we could speculate on a synergistic effect of compound heterozygosity that could explain the different phenotype observed in this family.

Phenotype variability in a large Spanish family with Alport syndrome associated with novel mutations in COL4A3 gene