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

Prince, Samantha (2013). Mutation analysis of wolfram syndrome patients and functional study of the Wolframin protein. University of Birmingham. Ph.D.

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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.