Candidate gene studies in pedigrees with maturity-onset diabetes of the young not linked with glucokinase

Zhang, Y.; Warren-Perry, Margaret; Saker, P. J.; Hattersley, Andrew T.; Mackie, Anna; Baird, J D; Greenwood, Richard; Stoffel, Markus; Bell, Graeme I.

doi:10.1007/bf00402175

Cited by 13 publications

(8 citation statements)

References 33 publications

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“…Glucokinase is essential for glucose metabolism in the ␤ cell; some mutations in the glucokinase gene reduce the affinity of the enzyme for glucose resulting in a small increase in the plasma glucose concentrations (11). While this subtype accounts for 60% of MODY in France (12), it is less prevalent elsewhere (13,14). Recently, MODY3 was identified by linkage to a region on the long arm of chromosome 12 (15).…”

Section: Non-insulin-dependent Diabetes Mellitus (Niddm)mentioning

confidence: 99%

Characterization of the MODY3 phenotype. Early-onset diabetes caused by an insulin secretion defect.

Lehto¹,

Tuomi²,

Mahtani³

et al. 1997

J. Clin. Invest.

190

155

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Maturity-onset diabetes of the young (MODY) type 3 is a dominantly inherited form of diabetes, which is often misdiagnosed as non-insulin-dependent diabetes mellitus (NIDDM) or insulin-dependent diabetes mellitus (IDDM). Phenotypic analysis of members from four large Finnish MODY3 kindreds (linked to chromosome 12q with a maximum lod score of 15) revealed a severe impairment in insulin secretion, which was present also in those normoglycemic family members who had inherited the MODY3 gene. In contrast to patients with NIDDM, MODY3 patients did not show any features of the insulin resistance syndrome. They could be discriminated from patients with IDDM by lack of glutamic acid decarboxylase antibodies (GAD-Ab). Taken

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Section: Non-insulin-dependent Diabetes Mellitus (Niddm)mentioning

confidence: 99%

Characterization of the MODY3 phenotype. Early-onset diabetes caused by an insulin secretion defect.

Lehto¹,

Tuomi²,

Mahtani³

et al. 1997

J. Clin. Invest.

190

155

View full text Add to dashboard Cite

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“…Linkage to MODY3 was found in 50% of the remaining nonglucokinase families (8), suggesting a prevalence of <25%. In contrast, glucokinase mutations are uncommon in U.K. MODY (11%) (13,14) and Japanese early onset NIDDM (0.5%) (15). It has been suggested that the difference between France and the U.K. reflects ascertainment differences resulting in a milder phenotype being more commonly collected in France (3,13).…”

mentioning

confidence: 99%

Mutations in the Hepatocyte Nuclear Factor–1α Gene Are a Common Cause of Maturity-Onset Diabetes of the Young in the U.K.

et al. 1997

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Mutations in the hepatocyte nuclear factor-la (HNFl a ) gene have recently been shown to cause maturityonset diabetes of the young (MODY). We have examined 15 U.K. MODY families for mutations in the coding region of the HNF-la gene. Eight different mutations, three frameshift (P291fsinsC, P379fsdelCT, and A443fsdelCA) and five missense mutations (P129T, R131W, R159W, P519L, and T620I), were identified in eleven families (73%). The previously reported mutation P291fsinsC was found in four pedigrees. A screen of a further 32 probands with early onset (<40 years of age) NIDDM showed the mutation in two additional families. This common mutation was present on at least three different haplotypes, suggesting that its high frequency is due to recurrent mutation rather than a founder effect. We have demonstrated that mutations in the HNF-la gene are a common cause of MODY in U.K. families and result in early onset NIDDM with a progressive clinical course. Mutation-based genetic counseling can now be considered for the majority of patients with MODY. Diabetes 46:720-725,1997

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“…They code for the enzyme glucokinase (GGK/MODY2) (4) or for the transcription factors hepatocyte nuclear factor 4 alpha (HNF-4a/MODY1) (5), hepatocyte nuclear factor 1 alpha (HNF-1a/MODY3) (6), insulin promoter factor 1 (IPF1/MODY4) (7) and hepatocyte nuclear factor 1 beta (HNF-1b/MODY5) (8). The relative prevalences of the different subtypes of MODY have been shown to vary greatly in studies of British, French and German populations (9)(10)(11)(12)(13). MODY2 represents from 8 to 63% of cases (the most prevalent form in France) and MODY3 from 21 to 64% of cases (the most prevalent form in England).…”

Section: Introductionmentioning

confidence: 99%

Genetic and clinical characterisation of maturity-onset diabetes of the young in Spanish families

Costa

Bescós²,

Velho³

et al. 2000

European Journal of Endocrinology

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Objective: To investigate the frequencies of the major maturity-onset diabetes of the young (MODY) subtypes in a panel of Spanish families and to assess phenotypic differences in patients with the different subtypes of MODY. Methods: Forty-eight subjects from twenty families with clinical diagnosis of MODY were studied. They underwent a standardised clinical examination and a 75-g oral glucose tolerance test (OGTT) was performed. Estimations of insulin sensitivity (%S) and insulin secretion capacity (%B) were calculated by the computer-solved homeostasis model assessment (HOMA). Mutations in the coding regions of hepatocyte nuclear factor (HNF)-4a/MODY1, glucokinase (GCK/MODY2) and HNF-1a/MODY3 genes were investigated by single strand comformation polymorphism and sequencing analysis. Results: Mutations in the GCK and HNF-1a genes were observed in 5 (25%) and 7 (35%) families respectively. Novel mutations included R385X, M238fsdelT, V226fsdelTinsAA and S418-7del11 in the GCK gene, and S121fsdelC, V133 M, R159Q and V259D in the HNF-1a gene. No MODY1 families were found. Subjects which were neither MODY2 nor MODY3 (MODY-X) had a higher fasting glucose than subjects in the other groups. Insulin secretion capacity was similar in the three groups and the insulin sensitivity was decreased in MODY-X subjects. Glucose levels were significantly higher and insulin levels significantly lower, throughout the OGTT, in MODY3 compared with MODY2 subjects. Conclusions: Mutations in the GCK/MODY2 and HNF-1a/MODY3 genes account for the majority of cases in a panel of Spanish MODY families, with MODY3 being the most frequent subtype. The relative frequencies and the clinical characteristics of these MODY subtypes are in agreement with data previously reported in other European populations. MODY-X patients seem to present a heterogeneous clinical profile.

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Candidate gene studies in pedigrees with maturity-onset diabetes of the young not linked with glucokinase

Cited by 13 publications

References 33 publications

Characterization of the MODY3 phenotype. Early-onset diabetes caused by an insulin secretion defect.

Characterization of the MODY3 phenotype. Early-onset diabetes caused by an insulin secretion defect.

Mutations in the Hepatocyte Nuclear Factor–1α Gene Are a Common Cause of Maturity-Onset Diabetes of the Young in the U.K.

Genetic and clinical characterisation of maturity-onset diabetes of the young in Spanish families

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