Journal Article

Somatic mosaicism for a mutation of the <i>COL4A5</i> gene is a cause of mild phenotype male Alport syndrome*

Rafal Przybyslaw Krol, Kandai Nozu, Koichi Nakanishi, Kazumoto Iijima, Yasuhiro Takeshima, Xue Jun Fu, Yoshimi Nozu, Hiroshi Kaito, Kyoko Kanda, Masafumi Matsuo and Norishige Yoshikawa

in Nephrology Dialysis Transplantation

Published on behalf of European Renal Association - European Dialysis and Transplant Assoc

Volume 23, issue 8, pages 2525-2530
Published in print August 2008 | ISSN: 0931-0509
Published online March 2008 | e-ISSN: 1460-2385 | DOI: http://dx.doi.org/10.1093/ndt/gfn005
Somatic mosaicism for a mutation of the COL4A5 gene is a cause of mild phenotype male Alport syndrome*

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Background. Alport syndrome is the most common form of hereditary nephritis and is mainly caused by mutations in the COL4A5 gene, which shows the X-linked form. It is well known that some male Alport syndrome cases show a relatively mild phenotype, but few molecular investigations have been conducted to clarify the mechanism of this phenotype.

Methods and results. This report concerns an 8-year-old male sporadic Alport syndrome patient. While electron microscopy of the glomerular basement membrane showed typical findings for Alport syndrome, however, the immunohistochemical analysis of the glomerulus showed mosaic staining of the type IV collagenα5 chain. The mutational analysis of the COL4A5 gene unexpectedly disclosed two peaks at the intron 43 splicing acceptor site (c. 3998-2 a/t) with direct sequencing. Restriction enzyme analysis demonstrated that the presence of somatic mosaicism was responsible for this mutation. mRNA extracted from the urinary sediments was analysed by RT-PCR and two PCR fragments were amplified, one consisting of a normal sequence and one with skipping of exon 44.

Conclusions. Our findings indicate that somatic mosaicism for COL4A5 is responsible for male X-linked Alport syndrome with an α5 mosaic staining pattern. Several cases with somatic mosaicism have previously been reported, however, this is the first case where the presence of this mutation was proved with a comprehensive analysis of genomic DNA, mRNA and α5 expression in the tissues. Somatic mosaicism may thus be one of the causes of the mild phenotype in Alport syndrome.

Keywords: Alport syndrome; COL4A5; somatic mosaicism

Journal Article.  3163 words.  Illustrated.

Subjects: Nephrology

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