Autosomal Dominant Diabetes Arising From a Wolfram Syndrome 1 Mutation

Abstract

We used an unbiased genome-wide approach to identify exonic variants segregating with diabetes in a multigenerational Finnish family. At least eight members of this family presented with diabetes with age of diagnosis ranging from 18 to 51 years and a pattern suggesting autosomal dominant inheritance. We sequenced the exomes of four affected members of this family and performed follow-up genotyping of additional affected and unaffected family members. We uncovered a novel nonsynonymous variant (p.Trp314Arg) in the Wolfram syndrome 1 (WFS1) gene that segregates completely with the diabetic phenotype. Multipoint parametric linkage analysis with 13 members of this family identified a single linkage signal with maximum logarithm of odds score 3.01 at 4p16.2-p16.1, corresponding to a region harboring the WFS1 locus. Functional studies demonstrate a role for this variant in endoplasmic reticulum stress, which is consistent with the β-cell failure phenotype seen in mutation carriers. This represents the first compelling report of a mutation in WFS1 associated with dominantly inherited nonsyndromic adult-onset diabetes.

A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome

“…WFS1 gene variants are also associated with a risk of type 2 diabetes (17). Moreover, a specific WFS1 variant can cause autosomal dominant diabetes (18), raising the possibility that this rare disorder is relevant to common molecular mechanisms altered in diabetes and other human chronic diseases in which ER dysfunction is involved.…”

Association of Wolfram syndrome with Fallot tetralogy in a girl

“…However, recently, a dominantly inherited WFS1 mutation was found to underlie Wolfram syndrome in a Finnish family. 9 Mutations in CISD2 have been identified in patients with a similar clinical picture but without diabetes insipidus (Wolfram syndrome 2). 10 Similar to wolframin, the CISD2-encoded protein ERIS (endoplasmic reticulum intermembrane small protein) localizes to endoplasmic reticulum.…”

Clinical utility gene card for: Wolfram syndrome

“…18 However, due to the variable order and age of onset of different clinical features, care has to be taken with the interpretation of heterozygous variants in WFS1, which cause Wolfram-like syndrome disorders, including missense mutations associated with autosomal dominant OA and sensorineural hearing loss, 10,19 autosomal dominant nonsyndromic adult-onset diabetes, 20 psychiatric symptoms and autosomal dominant low-frequency nonsyndromic sensorineural hearing loss. 21 In a systematic review, analysing the published clinical data in 392 patients with WFS, 98.2% had DM and 82.14% developed OA.…”