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NDT Advance Access published online on March 3, 2006
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfl051
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received July 12, 2005
Accepted January 27, 2006

Original Article

Tissue-specific distribution of an alternatively spliced COL4A5 isoform and non-random X chromosome inactivation reflect phenotypic variation in heterozygous X-linked Alport syndrome

Yoshio Shimizu 1 *, Michio Nagata 1, Joichi Usui 1, Kouichi Hirayama 1, Keigyo Yoh 1, Kunihiro Yamagata 1, Masaki Kobayashi 2, and Akio Koyama 3

1 Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
2 Department of Nephrology, Tokyo Medical University Kasumigaura Hospital, 3-20-1 Chuo, Ami, Ibaraki 300-0332, Japan
3 Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; Ibaraki Prefectural University of Health Sciences, 4669 Ami, Ami, Ibaraki 300-0394, Japan

* To whom correspondence should be addressed.
Yoshio Shimizu, E-mail: y-shimz{at}md.tsukuba.ac.jp



  Abstract

A novel type of hereditary transmission of COL4A5 in a Japanese family with X-linked Alport syndrome was detected through analysis of cDNA sequences and an X-chromosome inactivation assay. A female patient with moderately altered renal function, who was diagnosed with Alport syndrome by renal biopsy, and her mother, who was undergoing maintenance haemodialysis, showed similar tissue-specific expression of a truncated isoform of COL4A5, which was generated by alternative splicing without a splice-site mutation. Expression of the truncated isoform occurred in the renal specimen derived from the patient, but not in specimens from controls. Genomic analysis revealed two point mutations (c.4821 + 121, T>C; c.4822-151_150, ins T) in intron 49 of COL4A5 from the patient. The peripheral blood mononuclear cells of the patient and her mother showed non-random lyonization. While the females showed only renal impairment, an affected male in the same family suffered from severe renal insufficiency, visual defect and hearing disturbances. Hence, we suggest that this type of heredity COL4A5 presents with phenotypic variation in female heterozygous X-linked Alport syndrome patients.

Keywords: alport syndrome; alternatively spliced isoform; COL4A5; X-chromosome inactivation.
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