title: Reassessment of the putative role of BLK-p.A71T loss-of-function mutation in MODY and type 2 diabetes.
abstract: OBJECTIVE
  MODY is believed to be caused by at least 13 different genes. Five rare mutations at the BLK locus, including only one non-synonymous p.A71T variant, were reported to segregate with diabetes in three MODY families. The p.A71T mutation was shown to abolish the enhancing effect of BLK on insulin content and secretion from pancreatic beta cell lines. Here, we reassessed the contribution of BLK to MODY and tested the effect of BLK-p.A71T on type 2 diabetes risk and variations in related traits.
  
  
  METHODS
  BLK was sequenced in 64 unelucidated MODY samples. The BLK-p.A71T variant was genotyped in a French type 2 diabetes case-control study including 4,901 cases and 4,280 controls, and in the DESIR (Data from an Epidemiological Study on the Insulin Resistance Syndrome) and SUVIMAX (Supplementation en Vitamines et Mineraux Antioxydants) population-based cohorts (n = 6,905). The variant effects were assessed by logistic and linear regression models.
  
  
  RESULTS
  No rare non-synonymous BLK mutations were found in the MODY patients. The BLK p.A71T mutation was present in 52 normoglycaemic individuals, making it very unlikely that this loss-of-function mutation causes highly penetrant MODY. We found a nominal association between this variant and increased type 2 diabetes risk, with an enrichment of the mutation in the obese diabetic patients, although no significant association with BMI was identified.
  
  
  CONCLUSIONS
  No mutation in BLK was found in our MODY cohort. From our findings, the BLK-p.A71T mutation may weakly influence type 2 diabetes risk in the context of obesity; however, this will require further validation.
authors.affiliation: CNRS-UMR-8199, Lille Pasteur Institute, 1 rue du Professeur Calmette, 59019 Lille Cedex, France.
authors.forename: A
authors.initials: A
authors.lastname: Bonnefond
authors.forename: L
authors.initials: L
authors.lastname: Yengo
authors.forename: J
authors.initials: J
authors.lastname: Philippe
authors.forename: A
authors.initials: A
authors.lastname: Dechaume
authors.forename: I
authors.initials: I
authors.lastname: Ezzidi
authors.forename: E
authors.initials: E
authors.lastname: Vaillant
authors.forename: A P
authors.initials: AP
authors.lastname: Gjesing
authors.forename: E A
authors.initials: EA
authors.lastname: Andersson
authors.forename: S
authors.initials: S
authors.lastname: Czernichow
authors.forename: S
authors.initials: S
authors.lastname: Hercberg
authors.forename: S
authors.initials: S
authors.lastname: Hadjadj
authors.forename: G
authors.initials: G
authors.lastname: Charpentier
authors.forename: O
authors.initials: O
authors.lastname: Lantieri
authors.forename: B
authors.initials: B
authors.lastname: Balkau
authors.forename: M
authors.initials: M
authors.lastname: Marre
authors.forename: O
authors.initials: O
authors.lastname: Pedersen
authors.forename: T
authors.initials: T
authors.lastname: Hansen
authors.forename: P
authors.initials: P
authors.lastname: Froguel
authors.forename: M
authors.initials: M
authors.lastname: Vaxillaire
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D009154:Mutation; D055815:Young Adult; D019061:src-Family Kinases
chemical_list: C082599:protein-tyrosine kinase p55(blk); D019061:src-Family Kinases