Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus

Abstract

Maturity-onset diabetes of the young (MODY) is a form of non-insulin-dependent (type 2) diabetes mellitus (NIDDM) which is characterized by an early age at onset and an autosomal dominant mode of inheritance. Except for these features, the clinical characteristics of patients with MODY are similar to those with the more common late-onset form(s) of NIDDM. Previously we observed tight linkage between DNA polymorphisms in the glucokinase gene on the short arm of chromosome 7 and NIDDM in a cohort of sixteen French families having MODY. Glucokinase is an enzyme that catalyses the formation of glucose-6-phosphate from glucose and may be involved in the regulation of insulin secretion and integration of hepatic intermediary metabolism. Because the glucokinase gene was a candidate for the site of the genetic lesion in these families, we scanned this gene for mutations. Here we report the identification of a nonsense mutation in the gene encoding glucokinase and its linkage with early-onset diabetes in one family. To our knowledge, this result is the first evidence implicating a mutation in a gene involved in glucose metabolism in the pathogenesis of NIDDM.

Improved metabolic disorders of insulin receptor-deficient mice by transgenic overexpression of glucokinase in the liver

“…GK is a key regulator in the hepatic control of glucose storage and disposal [6,24]. Since GK gene expression was decreased in some diabetic patients [8,9,10], increasing GK activity in the liver appeared as an attractive approach to normalize hyperglycaemia, a common feature of both Type I and Type II diabetes. Hyperglycaemia is the main factor responsible for the development of diabetes-associated retinal, renal, neurological and vascular complications [25].…”

“…Studies focused on GK gained particular attention since the discovery that MODY-2 is associated with mutations in the GK gene resulting in reduced GK activity in both liver and beta cells [8,9]. Lower hepatic GK activity was also reported in a group of patients with Type II (non-insulin-dependent) diabetic mellitus patients [10].…”

Glucokinase and candidate genes for Type 2 (non-insulin-dependent) diabetes mellitus

“…Population association studies of the GK gene locus between normoglycaemic and Type 2 diabetic American Blacks [72] and Mauritian Creoles [73] have been positive. Mutations have now been recorded in some families with MODY (Type 2 diabetes subtype presenting from the second decade with an autosomal dominant mode of inheritence) [41, [74][75][76]) and in one pedigree thought to have classic Type 2 diabetes [77] but no other mutations have yet been identified in the common variety of the disease.…”

“…In the French study a nonsense mutation in exon 7 of the GK gene was identified [GAG (Glu) to TAG (amber termination codon)] [75] together with two further missense mutations in exon 7 (Thr-228--->Met and Gly-261--+Arg) that cosegregate with diabetes [41]. In the UK study a missense mutation in exon 8 was identified (Gly-299--->Arg) [77].…”

Deletion of the donor splice site of intron 4 in the glucokinase gene causes maturity-onset diabetes of the young.

“…16 different nonsense and missense mutations in the glucokinase gene have been identified in affected members ofthese MODY families (6)(7)(8)(9). These mutations were shown to impair the enzymatic activity of the encoded protein (10).…”