title: 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.
authors.affiliation: National Human Genome Research Institute, Bethesda, Maryland.
authors.forename: Lori L
authors.initials: LL
authors.lastname: Bonnycastle
authors.forename: Peter S
authors.initials: PS
authors.lastname: Chines
authors.forename: Takashi
authors.initials: T
authors.lastname: Hara
authors.forename: Jeroen R
authors.initials: JR
authors.lastname: Huyghe
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Swift
authors.forename: Pirkko
authors.initials: P
authors.lastname: Heikinheimo
authors.forename: Jana
authors.initials: J
authors.lastname: Mahadevan
authors.forename: Sirkku
authors.initials: S
authors.lastname: Peltonen
authors.forename: Hanna
authors.initials: H
authors.lastname: Huopio
authors.forename: Pirjo
authors.initials: P
authors.lastname: Nuutila
authors.forename: Narisu
authors.initials: N
authors.lastname: Narisu
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Goldfeder
authors.forename: Michael L
authors.initials: ML
authors.lastname: Stitzel
authors.forename: Simin
authors.initials: S
authors.lastname: Lu
authors.forename: Michael
authors.initials: M
authors.lastname: Boehnke
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Urano
authors.forename: Francis S
authors.initials: FS
authors.lastname: Collins
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
mesh_terms: D000293:Adolescent; D000328:Adult; D003920:Diabetes Mellitus / Q000235:genetics*; D059865:Endoplasmic Reticulum Stress; D059472:Exome / Q000235:genetics; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D010375:Pedigree; D014929:Wolfram Syndrome / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; C114987:wolframin protein
references.citation: Nature. 2012 Nov 1;491(7422):56-65
references.pmid: 23128226
references.citation: Hum Mol Genet. 2001 Oct 15;10(22):2509-14
references.pmid: 11709538
references.citation: J Biol Chem. 2005 Nov 25;280(47):39609-15
references.pmid: 16195229
references.citation: Curr Opin Pediatr. 2012 Aug;24(4):512-7
references.pmid: 22790102
references.citation: Biochem Biophys Res Commun. 2000 Feb 16;268(2):612-6
references.pmid: 10679252
references.citation: Lancet. 1995 Dec 2;346(8988):1458-63
references.pmid: 7490992
references.citation: Nucleic Acids Res. 2010 Sep;38(16):e164
references.pmid: 20601685
references.citation: Nat Cell Biol. 2012 Oct;14(10):1105-12
references.pmid: 22983116
references.citation: J Med Genet. 2006 May;43(5):435-40
references.pmid: 16648378
references.citation: Hum Mol Genet. 2001 Oct 15;10(22):2501-8
references.pmid: 11709537
references.citation: PLoS One. 2012;7(5):e38050
references.pmid: 22662265
references.citation: Diabetologia. 2008 Mar;51(3):458-63
references.pmid: 18040659
references.citation: Clin Genet. 2011 Feb;79(2):103-17
references.pmid: 20738327
references.citation: Nat Genet. 2007 Aug;39(8):951-3
references.pmid: 17603484
references.citation: Best Pract Res Clin Endocrinol Metab. 2012 Apr;26(2):171-87
references.pmid: 22498247
references.citation: J Clin Invest. 2010 Mar;120(3):744-55
references.pmid: 20160352
references.citation: Bioinformatics. 2009 Jul 15;25(14):1754-60
references.pmid: 19451168
references.citation: Hum Mol Genet. 2003 Aug 15;12(16):2003-12
references.pmid: 12913071
references.citation: J Mol Med (Berl). 2005 Jul;83(7):553-60
references.pmid: 15912360
references.citation: J Hum Genet. 2007;52(6):510-515
references.pmid: 17492394
references.citation: Bioinformatics. 2005 Aug 15;21(16):3445-7
references.pmid: 15947021
references.citation: Nat Genet. 2002 Jan;30(1):97-101
references.pmid: 11731797
references.citation: Expert Rev Mol Diagn. 2011 Apr;11(3):313-20
references.pmid: 21463240
references.citation: Islets. 2010 Jan-Feb;2(1):1-9
references.pmid: 21099287
references.citation: Cell. 2012 Mar 16;148(6):1160-71
references.pmid: 22424227
references.citation: Diabet Med. 2008 Jun;25(6):657-61
references.pmid: 18544103
references.citation: Hum Mol Genet. 2008 Dec 15;17(24):4012-21
references.pmid: 18806274
references.citation: Genome Res. 2012 Sep;22(9):1760-74
references.pmid: 22955987
references.citation: Eur J Hum Genet. 2005 Dec;13(12):1275-84
references.pmid: 16151413
references.citation: Curr Opin Endocrinol Diabetes Obes. 2011 Aug;18(4):252-8
references.pmid: 21844708
references.citation: Genome Res. 2010 Oct;20(10):1420-31
references.pmid: 20810667
references.citation: Nature. 2011 May 5;473(7345):43-9
references.pmid: 21441907
references.citation: Am J Hum Genet. 2007 Sep;81(3):559-75
references.pmid: 17701901