X-linked Alport syndrome associated with a synonymous p.Gly292Gly mutation alters the splicing donor site of the type IV collagen alpha chain 5 gene
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X-linked Alport syndrome (XLAS) is a progressive hereditary nephropathy caused by mutations in the type IV collagen alpha chain 5 gene (COL4A5). Although many COL4A5 mutations have previously been identified, pathogenic synonymous mutations have not yet been described.
A family with XLAS underwent mutational analyses of COL4A5 by PCR and direct sequencing, as well as transcript analysis of potential splice site mutations. In silico analysis was also conducted to predict the disruption of splicing factor binding sites. Immunohistochemistry (IHC) of kidney biopsies was used to detect α2 and α5 chain expression.
We identified a hemizygous point mutation, c.876A>T, in exon 15 of COL4A5 in the proband and his brother, which is predicted to result in a synonymous amino acid change, p.(Gly292Gly). Transcript analysis showed that this mutation potentially altered splicing because it disrupted the splicing factor binding site. The kidney biopsy of the proband showed lamellation of the glomerular basement membrane (GBM), while IHC revealed negative α5(IV) staining in the GBM and Bowman’s capsule, which is typical of XLAS.
This is the first report of a synonymous COL4A5 substitution being responsible for XLAS. Our findings suggest that transcript analysis should be conducted for the future correct assessment of silent mutations.
KeywordsSynonymous mutation COL4A5 Splicing Silent mutation
This study was supported by a grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Subject ID: 15K09691 to Kandai Nozu) and a Health Labour Sciences Research Grant for Research on Measures for Intractable Diseases (H26-nanchitou-ippan-036 to Kazumoto Iijima).
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Conflict of interest
Kandai Nozu has received lecture fees from Novartis Pharma K.K. and Taisho Pharm. Co. Kazumoto Iijima has received grants from Pfizer Japan, Inc., Daiichi Sankyo Co., Ltd., Japan Blood Product Organization, Miyarisan Pharmaceutical Co., Ltd., AbbVie LLC, CSL Behring, JCR Pharmaceuticals Co., Ltd., and Teijin Pharma Ltd.; lecture fees from MSD, ALEXION Pharmaceuticals, AstraZeneca K.K., Meiji Seika Pharma Co., Ltd., Novartis Pharma K.K., Zenyaku Kogyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Astellas Pharma Inc., Daiichi Sankyo, Co., Ltd., Springer Japan, and Asahi Kasei Pharma Corp; and consulting fees from Chugai Pharmaceutical Co., Ltd., Astellas Pharma Inc., and Takeda Pharmaceutical Company Ltd.
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