Autosomal dominant diabetes arising from a wolfram syndrome 1 mutation

Lori L. Bonnycastle, Peter S. Chines, Takashi Hara, Jeroen R. Huyghe, Amy J. Swift, Pirkko Heikinheimo, Jana Mahadevan, Sirkku Peltonen, Hanna Huopio, Pirjo Nuutila, Narisu Narisu, Rachel L. Goldfeder, Michael L. Stitzel, Simin Lu, Michael Boehnke, Fumihiko Urano, Francis S. Collins, Markku Laakso

Research output: Contribution to journalArticlepeer-review

97 Scopus citations

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.

Original languageEnglish
Pages (from-to)3943-3950
Number of pages8
JournalDiabetes
Volume62
Issue number11
DOIs
StatePublished - Nov 2013
Externally publishedYes

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