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Mutational spectrum of the WFS1 gene in Wolfram syndrome, nonsyndromic hearing impairment, diabetes mellitus, and psychiatric disease
Author(s) -
Cryns Kim,
Sivakumaran Theru A.,
Van den Ouweland Jody M.W.,
Pennings Ronald J.E.,
Cremers Cor W.R.J.,
Flothmann Kris,
Young TerryLynn,
Smith Richard J.H.,
Lesperance Marci M.,
Camp Guy Van
Publication year - 2003
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.10258
Subject(s) - wolfram syndrome , diabetes insipidus , genetics , biology , diabetes mellitus , sensorineural hearing loss , hearing loss , atrophy , allele , phenotype , gene , disease , medicine , endocrinology , audiology
Abstract WFS1 is a novel gene and encodes an 890 amino‐acid glycoprotein (wolframin), predominantly localized in the endoplasmic reticulum. Mutations in WFS1 underlie autosomal recessive Wolfram syndrome and autosomal dominant low frequency sensorineural hearing impairment (LFSNHI) DFNA6/14. In addition, several WFS1 sequence variants have been shown to be significantly associated with diabetes mellitus and this gene has also been implicated in psychiatric diseases. Wolfram syndrome is highly variable in its clinical manifestations, which include diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. Wolfram syndrome mutations are spread over the entire coding region, and are typically inactivating, suggesting that a loss of function causes the disease phenotype. In contrast, only non‐inactivating mutations have been found in DFNA6/14 families, and these mutations are mainly located in the C‐terminal protein domain. In this paper, we provide an overview of the currently known disease‐causing and benign allele variants of WFS1 and propose a potential genotype–phenotype correlation for Wolfram syndrome and LFSNHI. Hum Mutat 22:275–287, 2003. © 2003 Wiley‐Liss, Inc.