A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Autosomal Dominant Diabetes Arising From a Wolfram Syndrome 1 Mutation
Tekijät: Bonnycastle LL, Chines PS, Hara T, Huyghe JR, Swift AJ, Heikinheimo P, Mahadevan J, Peltonen S, Huopio H, Nuutila P, Narisu N, Goldfeder RL, Stitzel ML, Lu SM, Boehnke M, Urano F, Collins FS, Laakso M
Kustantaja: AMER DIABETES ASSOC
Julkaisuvuosi: 2013
Journal: Diabetes
Tietokannassa oleva lehden nimi: DIABETES
Lehden akronyymi: DIABETES
Numero sarjassa: 11
Vuosikerta: 62
Numero: 11
Aloitussivu: 3943
Lopetussivu: 3950
Sivujen määrä: 8
ISSN: 0012-1797
DOI: https://doi.org/10.2337/db13-0571
Tiivistelmä
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 -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.
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 -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.
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