Mutation analysis of wolfram syndrome patients and functional study of the Wolframin protein

Abstract

Mutations of the WFS1 gene are responsible for most cases of Wolfram syndrome (WS), a rare, recessively inherited neurodegenerative disorder characterised by juvenile-onset nonautoimmune diabetes mellitus and optic atrophy. Variants of \(\char{cmti10}{0x57}\)\(\char{cmti10}{0x46}\)\(\char{cmti10}{0x53}\)\(\char{cmti10}{0x31}\) are also associated with non-syndromic hearing loss and type-2 diabetes. Understanding the function of the \(\char{cmti10}{0x57}\)\(\char{cmti10}{0x46}\)\(\char{cmti10}{0x53}\)\(\char{cmti10}{0x31}\) protein-product wolframin, would enable developments in targeted therapy for WS patients and important insights to its possible contribution to type-2 diabetes pathogenesis. This study was aimed at expanding the spectrum of WS-associated genetic mutations and clinical data, and investigating the molecular mechanisms responsible for phenotypic variation associated with \(\char{cmti10}{0x57}\)\(\char{cmti10}{0x46}\)\(\char{cmti10}{0x53}\)\(\char{cmti10}{0x31}\)- mutation. The mutational and phenotypic spectrum of WS is broadened by our report of novel \(\char{cmti10}{0x57}\)\(\char{cmti10}{0x46}\)\(\char{cmti10}{0x53}\)\(\char{cmti10}{0x31}\) mutations and a case of \(\char{cmti10}{0x57}\)\(\char{cmti10}{0x46}\)\(\char{cmti10}{0x53}\)\(\char{cmti10}{0x32}\)-associated WS. New perspectives on the molecular mechanisms linking mutation to disease manifestation are also taken by characterisation of representative WFS1 mutations specific to phenotype, identification of potentially novel \(\char{cmti10}{0x57}\)\(\char{cmti10}{0x46}\)\(\char{cmti10}{0x53}\)\(\char{cmti10}{0x31}\) interacting partners, and the first evidence linking WFS1 with the exocrine pancreas. Our data suggests that some \(\char{cmti10}{0x57}\)\(\char{cmti10}{0x46}\)\(\char{cmti10}{0x53}\)\(\char{cmti10}{0x31}\)-mutations may allow residual protein function and these findings lay the groundwork for future functional investigation of mutated wolframin to explore this hypothesis further.