Missense glucokinase mutation in maturity–onset diabetes of the young and mutation screening in late–onset diabetes

Stoffel, Markus; Patel, P.; Lo, Yuk-ming Dennis; Hattersley, Andrew T.; Lucassen, Anneke; Page, R.; Bell, James B.; Bell, Graeme I.; Turner, R. Elaine; Wainscoat, James S.

doi:10.1038/ng1092-153

Cited by 125 publications

(87 citation statements)

References 17 publications

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“…2). They have been found in subjects of many different racial and ethnic backgrounds including Caucasians (Brazil [this report], France [4,10,11], Italy [20], Sweden [21], Switzerland [22], United Kingdom [23], and United States [24] ), Asians (Japan [15,16,25] ), blacks (Congo [11] ), and admixed populations (African-American [21,26] and Puerto Rican [24] ). The majority of the mutations identified to date have been described in only a single family suggesting that the present list is not exhaustive and that new mutations will continue to be found.…”

Section: Discussionmentioning

confidence: 99%

Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families

et al. 1997

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Maturity-onset diabetes of the young (MODY) is a form of non-insulin-dependent diabetes mellitus (NIDDM) characterized by early onset, usually before 25 years of age and often in adolescence, and by autosomal dominant inheritance [1]. Although commonly thought to be a relatively rare form of NIDDM, recent studies suggest that it may not be that uncommon and 2-5 % of patients with NIDDM may in fact have MODY [2]. Mutations in genes on chromosomes 20, 7 and 12, designated MODY1, MODY2/glucokinase (GCK) and MODY3, respectively, can cause this form of diabetes [3][4][5]. Moreover, there are likely to be additional MODY genes since there are families in which MODY does not cosegregate with markers tightly linked to the three known MODY loci [5]. Diabetologia (1997) Summary Mutations in glucokinase are associated with defects in insulin secretion and hepatic glycogen synthesis resulting in mild chronic hyperglycaemia, impaired glucose tolerance or diabetes mellitus. We screened members of 35 families with features of maturity-onset diabetes of the young for mutations in the glucokinase gene and found 16 different mutations. They included 14 new mutations in the glucokinase gene: 9 missense mutations (A53S, G80A, H137R, T168P, M210T, C213R, V226M, S336L and V367M); 2 nonsense mutations (E248X and S360X); a deletion of one nucleotide resulting in a frameshift (V401del1); a substitution of a conserved nucleotide at a splice acceptor site (L122-1G → T); and a 10 base pair deletion that removed the GT of the splice donor site and the following eight nucleotides (K161 + 2del10). In addition, we found two previously identified mutations: R186X and G261R. Study of 260 subjects with glucokinase-deficient hyperglycaemia from 42 families with 36 different GCK mutations made it possible to define the clinical profile of this subtype of non-insulin-dependent diabetes mellitus (NIDDM). Hyperglycaemia due to glucokinase deficiency is often mild (fewer than 50 % of subjects have overt diabetes) and is evident during the early years of life. Despite the long duration of hyperglycaemia, glucokinase-deficient subjects have a low prevalence of micro-and macro-vascular complications of diabetes. Obesity, arterial hypertension and dyslipidaemia are also uncommon in this form of NIDDM. [Diabetologia (1997) 40: 217-224]

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Section: Discussionmentioning

confidence: 99%

Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families

et al. 1997

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“…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.…”

Section: Glucokinase and Candidate Genes For Type 2 Diabetesmentioning

confidence: 99%

“…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]. Molecular modelling studies suggest that mutation of Thr-228 may affect GK affinity for ATP and that Gly-261 mutation may affect glucose binding i.e.…”

Section: Glucokinase Gene Mutations In Type 2 Diabetesmentioning

confidence: 99%

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

Randle

1993

Diabetologia

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“…Several nonsense and missense mutations have recently been identified in the GCK gene as a cause of hyperglycemia in MODY (6,7,9) and in a few late-onset NIDDM families (8,24). We here report a deletion in the 5' splice site of intron 4 in the GCK gene that is responsible for diabetes in a French MODY family.…”

Section: Discussionmentioning

confidence: 78%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Sun¹,

Pueyo²,

Zouali³

et al. 1993

J. Clin. Invest.

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Missense and nonsense mutations in the glucokinase gene have recently been shown to result in maturity-onset diabetes of the young (MODY), a subtype of non-insulin-dependent diabetes mellitus with early age of onset. Glucokinase catalyzes the formation of glucose-6-phosphate and is involved in the regulation of insulin secretion and integration of hepatic intermediary metabolism. Nucleotide sequence analysis of exon 4 and its flanking intronic regions of the glucokinase gene, in four hyperglycemic individuals of a MODY family, revealed a deletion of 15 base pairs, which removed the t of the gt in the donor splice site of intron 4, and the following 14 base pairs. This deletion resulted in two aberrant transcripts, which were analyzed by reverse transcription of RNA from lymphoblastoid cells obtained from a diabetic patient. In one ofthe abnormal transcripts, exon 5 is missing, while in the other, the activation of a cryptic splice site leads to the removal of the last eight codons of exon 4. This intronic deletion in a donor splice site seems to cause a more severe form of glucose intolerance, compared with point mutations described in glucokinase. This might be due to a more pronounced effect on insulin secretion. (J. Clin. Invest. 1993.

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Missense glucokinase mutation in maturity–onset diabetes of the young and mutation screening in late–onset diabetes

Cited by 125 publications

References 17 publications

Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families

Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families

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

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

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