A large tandem duplication within the COL4A5 gene is responsible for the high prevalence of Alport syndrome in French Polynesia

A large tandem duplication within the COL4A5 gene is responsible for the high prevalence of Alport syndrome in French Polynesia. Background The prevalence of X-linked Alport syndrome, a progressive inherited nephropathy associated with mutations in the type IV collagen gene COL4A5 , is remarkably high in French Polynesia. Methods A vast clinical, genealogic, and molecular study was undertaken in Polynesia, based on public records, patients' interviews, linkage analysis, and mutation screening. Results and Conclusions We show that the high frequency of Alport syndrome in this region is due to a founder mutation that occurred onto a common haplotype shared by affected and unaffected individuals, the presence of which precludes indirect molecular diagnosis. We have characterized the mutation as a tandem duplication of 35 COL4A5 exons, resulting in a ∼65% increase in the length of the collagenous domain of the α5(IV) chain, which is still able to assemble into type IV collagen network as shown by immunofluorescence analysis. That mutation is associated with severe and highly penetrant ocular symptoms and with uniformly thin glomerular basememnt membrane (GBM) in male adult patients. However, the rate of progression of the renal disease is very variable from one male patient to another, demonstrating the importance of strong modifier factors. Our results suggest that the 20% to 50% of "missing" COL4A5 mutations in X-linked Alport syndrome may be rearrangements similar to that reported here, which was not detectable by sequencing of either individual COL4A5 exons or overlapping cDNA fragments. Finally, we provide the basis for a polymerase chain reaction (PCR) assay that accurately identifies female carriers and allows adequate genetic counseling in this population.