NDT Advance Access originally published online on March 10, 2008
Nephrology Dialysis Transplantation 2008 23(8):2525-2530; doi:10.1093/ndt/gfn005
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Somatic mosaicism for a mutation of the COL4A5 gene is a cause of mild phenotype male Alport syndrome*
1 Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo, 6500017 2 Department of Pediatrics, Wakayama Medical University, Wakayama, 6418509 3 Department of Nephrology, National Center for Child Health and Development, Tokyo, 1578535, Japan
Correspondence and offprint requests to: Kandai Nozu, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe 650-0017, Kusunokicho 7-5-1, Chuo, Kobe, Hyogo, Japan. Tel: +81-78-382-6090; Fax: +81-78-382-6099; E-mail: nozu{at}med.kobe-u.ac.jp
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Abstract |
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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 collagen
5 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 5 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 5 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
* All authors contributed equally to this study.
Received for publication: 15. 9.07
Accepted in revised form: 3. 1.08