Mutational spectrum of the WFS1 gene in Wolfram syndrome, nonsyndromic hearing impairment, diabetes mellitus, and psychiatric disease.

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