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

Abstract

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 approximately 65% increase in the length of the collagenous domain of the alpha 5(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 basement 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.

COL4A3/COL4A4 Mutations and Features in Individuals with Autosomal Recessive Alport Syndrome

“…9 Founder mutations have been described in the COL4A5 gene in North America in X-linked Alport syndrome, and other variants have also been reported in the COL4A3 and COL4A4 genes in Cyprus. [28][29][30] Only five individuals were known to be from consanguineous families but 12 had homozygous mutations. Two of these mutations, including p.(Ser969*), were found in multiple individuals and the homozygosity likely resulted from the high background prevalence of this variant rather than recent consanguinity.…”

Searching biomarker candidates in serum using multidimensional native chromatography. II Method evaluation with Alport syndrome and severe inflammation

“…The majority of cases are transmitted as an X-linked semidominant condition due to COL4A5 mutations [3,4]. Clinically, an individually variable progressive glomerulosclerosis, hypertension, hematuria, and proteinuria may occur with consequences ranging from nephrotic syndrome to end-stage renal disease.…”

Alport syndrome caused by inversion of a 21 Mb fragment of the long arm of the X-chromosome comprising exon 9 through 51 of the COL4A5 gene

“…More than 30 different larger structural COL4A5 rearrangements have so far been published. These rearrangements include deletions ranging from one or more exons (Antignac et al 1994;Barker et al 1990;Boye et al 1991;Ding et al 1994;Netzer et al 1992;Renieri et al 1992Renieri et al , 1995Saito et al 1994;Smeets et al 1992) to deletion of the whole gene (Antignac et al 1994;Netzer et al 1992), partial gene duplications (Arrondel et al 2004;Renieri et al 1995;Vetrie et al 1992), and combined partial gene deletion and duplication (Vetrie et al 1992). No frequent deletion breakpoints have been identified.…”

“…Smaller mutations deep into introns affecting the normal splicing will, however, not always be detected by Southern blotting analysis, but more likely by RNA analysis (King et al 2002). A very high frequency of X-linked AS in French Polynesia was found to be due to a COL4A5 founder mutation (Arrondel et al 2004). A large tandem duplication of the exons 2-36, located in intron 36, was solely detected by PFGE restriction mapping.…”

“…Splicing errors due to mutations deep into introns will solely be detected by RNA analysis, and larger genomic rearrangements by Southern blotting analysis or pulse-field gel electrophoresis (PFGE) (Arrondel et al 2004;King et al 2002).…”