Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus

Froguel, P; Vaxillaire, Martine; Sun, Fang; Velho, Gilberto; Zouali, Habib; Butel, M. O.; Lesage, S.; Vionnet, Nathalie; Korenbaum, Clément; Fougerousse, Françoise; Tanizawa, Yukio; Weissenbach, Jean; Beckmann, Jacques S.; Lathrop, G.M.; Passa, P; Permutt, M. A.; Cohen, Daniel

doi:10.1038/356162a0

Cited by 583 publications

(302 citation statements)

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“…In adulthood these beta cell defects, along with decreased insulin sensitivity would manifest itself in such a way that whole body glucose metabolism was affected. Individuals who have a rare monogenic form of diabetes known as 'maturity onset diabetes of the young' are proof of principle for this theory (7,8). The mutations in these individuals of the glucokinase gene leads to reduced birth weight and development of type 2 diabetes in early adulthood (9) caused by defective glucose sensing in the pancreatic beta cell …”

Section: Epidemiological Findingsmentioning

confidence: 99%

Fetal programming of glucose–insulin metabolism

Jones

Ozanne

2009

Molecular and Cellular Endocrinology

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Epidemiological studies have shown a link between poor fetal growth and increased risk of developing type 2 diabetes. These observations are highly reproducible in many populations worldwide although the mechanisms behind them remain elusive.The 'Thrifty Phenotype Hypothesis' was proposed to explain the underlying causes of these relationships. Animal models of poor intrauterine nutrition have been utilised to help to define the causal factors and identify the molecular mechanisms. Programmed changes in beta cell function and insulin action have been a common feature of animal models of poor intrauterine nutrition. Fundamental underlying mechanisms are starting to emerge, including changes in the epigenotype and mitochondrial function.

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Section: Epidemiological Findingsmentioning

confidence: 99%

Fetal programming of glucose–insulin metabolism

Jones

Ozanne

2009

Molecular and Cellular Endocrinology

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“…Given its central role in the regulation of insulin release, it is understandable that mutations in the gene encoding glucokinase (GCK) can cause both hyper-and hypoglycemia. Heterozygous inactivating mutations in GCK cause maturity-onset diabetes of the young (MODY), in which mild hyperglycemia is present at birth but often only detected later in life during screening for other purposes (2,3). Homozygous inactivating GCK mutations result in a more severe phenotype presenting at birth as permanent neonatal diabetes (4).…”

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confidence: 99%

Insights Into the Biochemical and Genetic Basis of Glucokinase Activation From Naturally Occurring Hypoglycemia Mutations

et al. 2003

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Glucokinase (GCK) is a key regulatory enzyme in the pancreatic ␤-cell and catalyzes the rate-limiting step for ␤-cell glucose metabolism. We report two novel GCK mutations (T65I and W99R) that have arisen de novo in two families with familial hypoglycemia. Insulin levels, although inappropriately high for the degree of hypoglycemia, remain regulated by fluctuations in glycemia, and pancreatic histology was normal. These mutations are within the recently identified heterotropic allosteric activator site in the theoretical model of human ␤-cell glucokinase. Functional analysis of the purified recombinant glutathionyl S-transferase fusion proteins of T65I and W99R GCK revealed that the kinetic changes result in a relative increased activity index (a measure of the enzyme's phosphorylating potential) of 9.81 and 6.36, respectively, compared with wild-type. The predicted thresholds for glucose-stimulated insulin release using mathematical modeling were 3.1 (T65I) and 2.8 (W99R) mmol/l, which were in line with the patients' fasting glucose. In conclusion, we have identified two novel spontaneous GCK-activating mutations whose clinical phenotype clearly differs from mutations in ATP-sensitive K ؉ channel genes. In vitro studies confirm the validity of structural and functional models of GCK and the putative allosteric activator site, which is a potential drug target for the treatment of type 2 diabetes.

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“…A possible explanation is that the genomic deletion of the 5'-splice site in intron 4 would affect the normal function of the transcriptional machinery, as it has been described by Leroux et al (32). The remaining sequence at the 5'-part ofintron 4 left after the deletion, gggcag (+ 1 to +6), could be recognized as a donor splice site and used with the intron 5 3'-acceptor splice site (ag), instead of the intron 4 (30). The third type of aberrant GCK messenger observed (with an insertion of the first 10 bp from intron 2 between exon 2/exon 3 and the skipping ofexon 5) seems to be rare, since we found it in only one RT-PCR experiment out of five.…”

Section: Discussionmentioning

confidence: 99%

“…The genomic deletion in intron 4 ofthe GCK gene is likely to be responsible for the hyperglycemia in kindred F423 for several reasons: (a) the defect in GCK cosegregated with diabetes in this family, and the likelihood of the odds score (lodscore) for linkage is highly significant (+4.85, i.e., odds for linkage of almost I0':1, data not shown) using an autosomal dominant model (6); (b) this deletion was not present in unrelated normal and late-onset NIDDM individuals; and (c) this deletion resulted in the synthesis of aberrant truncated GCK mRNA species, which probably encode a GCK enzyme with decreased or null activity. A molecular model of the glucokinase protein using the related yeast hexokinase B crystal structure has shown that the region encoded by exon 5, which is missing in splice variant I (Fig.…”

Section: Discussionmentioning

confidence: 99%

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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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Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus

Cited by 583 publications

References 20 publications

Fetal programming of glucose–insulin metabolism

Fetal programming of glucose–insulin metabolism

Insights Into the Biochemical and Genetic Basis of Glucokinase Activation From Naturally Occurring Hypoglycemia Mutations

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

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