Whole-Exome Sequencing and High Throughput Genotyping Identified KCNJ11 as the Thirteenth MODY Gene

Bonnefond, Amélie; Philippe, Julien; Durand, Emmanuelle; Dechaume, Aurélie; Huyvaert, Marlène; Montagne, Louise; Marre, Michel; Balkau, Beverley; Fajardy, I.; Vambergue, A.; Vatin, Vincent; Delplanque, Jérôme; Guilcher, David Le; Graeve, Franck De; Lecœur, Cécile; Sand, Olivier; Vaxillaire, Martine; Froguel, Philippe

doi:10.1371/journal.pone.0037423

Cited by 177 publications

(124 citation statements)

References 29 publications

Supporting

Mentioning

116

Contrasting

Unclassified

Order By: Relevance

“…In this study, we identified numerous elderly normoglycaemic carriers of the BLK-p.A71T mutation, which does not fit with either rarity and high penetrance of a MODY gene mutation or the usual clinical features [3,9,10]. Furthermore, we did not find any other coding mutations in two European cohorts that included 64 MODY patients.…”

Section: Discussioncontrasting

confidence: 54%

See 1 more Smart Citation

Reassessment of the putative role of BLK-p.A71T loss-of-function mutation in MODY and type 2 diabetes

Bonnefond¹,

Yengo²,

Philippe³

et al. 2012

Diabetologia

View full text Add to dashboard Cite

Aims/hypothesis 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 Electronic supplementary material The online version of this article

show abstract

Section: Discussioncontrasting

confidence: 54%

“…So far, 13 MODY genes have been identified [3]. Among these, BLK (MODY11) encodes a non-receptor tyrosinekinase of the SRC family of proto-oncogenes, which is present in many tissues and cells including pancreatic beta cells [4].…”

Section: Introductionmentioning

confidence: 99%

Reassessment of the putative role of BLK-p.A71T loss-of-function mutation in MODY and type 2 diabetes

Bonnefond¹,

Yengo²,

Philippe³

et al. 2012

Diabetologia

View full text Add to dashboard Cite

show abstract

“…At the molecular genetic level, MODY is defined by mutations in different genes, of which at least 13 are known. 4 The most common forms are HNF1A (MODY3, OMIM *600281), GCK (MODY2, OMIM *138079) and HNF4A (MODY1, OMIM *600281). 1 The various genetic subtypes differ in clinical manifestation: age of onset, pattern of hyperglycemia, response to treatment and associated extrapancreatic manifestations.…”

Section: Introductionmentioning

confidence: 99%

A decade of molecular genetic testing for MODY: a retrospective study of utilization in The Netherlands

et al. 2014

View full text Add to dashboard Cite

Genetic testing for maturity-onset diabetes of the young (MODY) may be relevant for treatment and prognosis in patients with usually early-onset, non-ketotic, insulin-sensitive diabetes and for monitoring strategies in non-diabetic mutation carriers. This study describes the first 10 years of genetic testing for MODY in The Netherlands in terms of volume and test positive rate, medical setting, purpose of the test and age of patients tested. Some analyses focus on the most prevalent subtype, HNF1A MODY. Data were retrospectively extracted from a laboratory database. In total, 502 individuals were identified with a pathogenic mutation in HNF4A, GCK or HNF1A between 2001 and 2010. Although mutation scanning for MODY was used at an increasing rate, cascade testing was only used for one relative, on average, per positive index patient. Testing for HNF1A MODY was mostly requested by internists and paediatricians, often from regional hospitals. Primary care physicians and clinical geneticists rarely requested genetic testing for HNF1A MODY. Clinical geneticists requested cascade testing relatively more often than other health professionals. A substantial proportion (currently 29%) of HNF1A MODY probands was at least 40 years old at the time of testing. In conclusion, the number of individuals genetically tested for MODY so far in The Netherlands is low compared with previously predicted numbers of patients. Doctors' valuation of the test and patients' and family members' response to (an offer of) genetic testing on the other hand need to be investigated. Efforts may be needed to develop and implement translational guidelines.

show abstract

“…Several monogenic forms of MODY have been identified, including MODY1-hepatocyte nuclear factor-4α (HNF4A), MODY2-glucokinase (GCK), MODY3-HNF1A, MODY4-pancreatic and duodenal homeobox 1 (PDX1) and MODY5-HNF1B (2). Carboxyl ester lipase (CEL) and paired box 4 (PAX4) have also been reported to be associated (3).…”

Section: Introductionmentioning

confidence: 99%

A novel mutation in the hepatocyte nuclear factor-1β gene in maturity onset diabetes of the young 5 with multiple renal cysts and pancreas hypogenesis: A case report

et al. 2017

Experimental and Therapeutic Medicine

View full text Add to dashboard Cite

Abstract.A 17-year-old Chinese male was hospitalized exhibiting hyperglycemia and increased serum urea nitrogen and creatinine levels in addition to weight loss. The patient was treated with gliclazide. The patient was 150 cm tall, weighed 35 kg and had no family history of diabetes or kidney disease. Physical examination revealed cephalus quadratus, rachitic rosary and a visible toe-out gait. Laboratory examinations revealed that the patient's fasting plasma glucose and glycosylated hemoglobin levels were markedly increased, fasting plasma C-peptide level was slightly increased and no peak 2 h postprandial was observed. Diabetic autoimmune antibodies [islet cell cytoplasmic autoantibodies (ICA), glutamic acid decarboxylase autoantibodies (GADA), isulinoma-2-associated autoantibodies (IA2A) and insulin autoantibodies (IAA)] were negative. Levels of serum electrolytes decreased, uric acid and parathyroid hormone increased, mild albuminuria was detected and there was a low proportion of urine. The patient also presented with low bone mass and cataracts. Abdominal computed tomography (CT) revealed a bilateral atrophic kidney with multiple renal cysts, primarily located at the junction of renal cortex and medulla, with a diameter of 0.3-0.7 cm. CT also revealed hypogenesis of the body and tail of the pancreas. In an oral glucose tolerance test, the mother and paternal uncle of the patient were diagnosed with type II diabetes and the patient's sister, maternal uncle and paternal grandpa were diagnosed with glucose tolerance impairment. Genetic testing revealed an unreported amino acid mutation in exon 2 of hepatocyte nuclear factor 1β (c.391C>T), a nonsense mutation of CAA to TAA at codon 131. This mutation was identified in the proband but not in any other family members.

show abstract

Whole-Exome Sequencing and High Throughput Genotyping Identified KCNJ11 as the Thirteenth MODY Gene

Cited by 177 publications

References 29 publications

Reassessment of the putative role of BLK-p.A71T loss-of-function mutation in MODY and type 2 diabetes

Reassessment of the putative role of BLK-p.A71T loss-of-function mutation in MODY and type 2 diabetes

A decade of molecular genetic testing for MODY: a retrospective study of utilization in The Netherlands

A novel mutation in the hepatocyte nuclear factor-1β gene in maturity onset diabetes of the young 5 with multiple renal cysts and pancreas hypogenesis: A case report

Contact Info

Product

Resources

About