Background: Wolfram syndrome (WS or DIDMOAD) is a rare (prevalence of 1/770,000) autosomal recessive multi-systemic neurodegenerative disease, characterized by non-autoimmune diabetes mellitus (DM) and optic atrophy. Additional features include diabetes insipidus (DI), sensorineural deafness, urinary tract abnormalities, ataxia, psychiatric illness, and other endocrine disturbances leading to death in mid-adulthood. This syndrome is caused by recessive mutations in the wolframin gene (WFS1) on chromosome 4p16.1. WFS1 encodes a trans-membrane protein localized to the endoplasmic reticulum (ER), suggesting that ER dysfunction is a major pathogenic component of WS. In WS, pancreatic β-cells and neuronal cells undergo apoptosis due to ER stress.
Objective and hypotheses: To describe the molecular basis of syndromic DM in two Turkish families.
Method: Two unrelated consanguineous Turkish families, with two affected children in each family were evaluated. In family 1; the two affected have DM, deafness and optic atrophy. In family two; the two affected have DM and deafness. None of the affected members of both families had diabetes insipidus. Homozygosity mapping (HZM) was performed followed by whole exome sequencing in the families.
Results: Two novel nonsense mutations were identified in WFS1 in each of the affected patients in family 1 (p.Y405X) and family 2 (p.W185X), leading to premature stop codons in exons 8 and 5 respectively. These novel exonic mutations lead to a mild form of WS in both families. All patients were found to be homozygous for the change, whereas parents and other unaffected siblings were carriers.
Conclusion: Our study expands the molecular spectrum of WFS1 mutations with two novel nonsense mutations in two unrelated consanguineous Turkish families. Therefore, detailed phenotypic and genotypic information may help to discover yet undisclosed genotypephenotype correlations in WS.
20 - 22 Sep 2014
European Society for Paediatric Endocrinology