A gene for maturity onset diabetes of the young (MODY) maps to chromosome 12q

Vaxillaire, Martine; Boccio, Valérie; Philippi, Anne; Vigouroux, Corinne; Terwilliger, J.; Passa, P; Beckmann, Jacques S.; Velho, Gilberto; Lathrop, G.M.; Froguel, Philippe

doi:10.1038/ng0495-418

Cited by 182 publications

(129 citation statements)

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“…This could, of course, indicate that the NPL scores represent random fluctuations, but it must also be taken into consideration that the parametric model might not be optimal because many of the parameters (mode of inheritance, penetrance, etc.) of MODYX are not known and might be expected to differ from MODY3 for which the model was initially specified (13). Another possible explanation is that EOD is polygenic rather than monogenic.…”

Section: Discussionmentioning

confidence: 99%

“…It could be argued that our sample size (29/26 families) is too small to detect linkage, especially if the disease is heterogeneous. However, it was possible to detect linkage to MODY1 and MODY3 using a small number of families with EOD (10,13). Families with EOD have proved successful for dissecting the genetics of other diseases such as breast cancer (35).…”

Section: Discussionmentioning

confidence: 99%

“…Second, we performed parametric multipoint analyses using the GENEHUNTER software (version 2.0). The parametric logarithm of odds (LOD) score and heterogeneity LOD (HLOD) score calculations were performed using an inheritance model proved successful in previous studies of early onset diabetes (MODY3) (13). Allele frequencies used in all of the analyses were those observed in the founders of the families in the study (30).…”

Section: Methodsmentioning

confidence: 99%

“…MODY1 (MIM#125850) is caused by mutations in the hepatocyte nuclear factor 4␣ gene (HNF-4␣; MIM*600281) on chromosome 20q (9,10). Mutations in the glucokinase (GCK; MIM*138079) gene on chromosome 7 cause a mild form of diabetes called MODY2 (MIM#125851) (11,12), whereas mutations in the HNF-1␣ (MIM*142410) gene on chromosome 12q account for the largest proportion of known MODY today, MODY3 (MIM#600496) (13,14). More recently, mutations in the insulin promoter factor-1 (IPF-1; MIM*600733) and HNF-1␤ (MIM*189907) genes have been identified as the causes of MODY4 and MODY5 (MIM#604284) (15,16).…”

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confidence: 99%

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Contribution of Known and Unknown Susceptibility Genes to Early-Onset Diabetes in Scandinavia

et al. 2002

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In an attempt to identify novel susceptibility genes predisposing to early-onset diabetes (EOD), we performed a genome-wide scan using 433 markers in 222 individuals (119 with diabetes) from 29 Scandinavian families with >2 members with onset of diabetes <45 years. The highest nonparametric linkage (NPL) score, 2.7 (P < 0.01), was observed on chromosome 1p (D1S473/D1S438). Six other regions on chromosomes 3p, 7q, 11q, 18q, 20q, and 21q showed a nominal P value <0.05. Of the EOD subjects in these 29 families, 20% were GAD antibody positive and 68% displayed type 1 diabetes HLA risk alleles (DQB*02 or 0302). Mutations in maturity-onset diabetes of the young (MODY) 1-5 genes and the A3243G mitochondrial DNA mutation were detected by single-strand conformation polymorphism and direct sequencing. To increase homogeneity, we analyzed a subsample of five families with autosomal dominant inheritance of EOD (greater than or equal to two members with age at diagnosis <35 years). The highest NPL scores were found on chromosome 1p (D1S438 -D1S1665; NPL 3.0; P < 0.01) and 16q (D16S419; NPL 2.9; P < 0.01). After exclusion of three families with MODY1, MODY3, and mitochondrial mutations, the highest NPL scores were observed on chromosomes 1p (D1S438; NPL 2.6; P < 0.01), 3p (D3S1620; NPL 2.2; P < 0.03), 5q (D5S1465; NPL 2.1; P < 0.03), 7q (D7S820; NPL 2.0; P < 0.03), 18q (D18S535; NPL 1.9; P < 0.04), 20q (D20S195; NPL 2.5; P < 0.02), and 21q (D21S1446; NPL 2.2; P < 0.03). We conclude that considerable heterogeneity exists in Scandinavian subjects with EOD; 24% had MODY or maternally inherited diabetes and deafness, and ϳ60% were GAD antibody positive or had type 1 diabetes-associated HLA genotypes. Our data also point at putative chromosomal regions, which could harbor novel genes that contribute to EOD. Diabetes

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Contribution of Known and Unknown Susceptibility Genes to Early-Onset Diabetes in Scandinavia

et al. 2002

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“…MODY2, located on chromosome 7p (4), is caused by mutations in the glucokinase gene (5). MODY3 was mapped to chromosome 12q (6) and is known to be caused by mutations in another transcription factor, HNF-la (7). Although the relative prevalence of these MODY subtypes varies regionally (8)(9)(10), families linked to chromosome 12q are the most frequently described.…”

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Novel Mutations and a Mutational Hotspot in the M0DY3 Gene

Glucksmann

Lehto²,

Tayber³

et al. 1997

Diabetes

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Maturity-onset diabetes of the young 3 (MODY3) is a type of NIDDM caused by mutations in the transcription factor hepatocyte nuclear factor-la (HNF-la) located on chromosome 12q. We have identified four novel HNF-la missense mutations in M0DY3 families. In four additional and unrelated families, we observed an identical insertion mutation that had occurred in a polycytidine tract in exon 4. Among those families, one exhibited a de novo mutation at this location. We propose that instability of this sequence represents a general mutational mechanism in M0DY3. We observed no HNFla mutations among 86 unrelated late-onset diabetic patients with relative insulin deficiency. Hence mutations in this gene appear to be most strongly associated with early-onset diabetes. Diabetes 46:1081-1086,1997MODY. The MODY1 locus, on chromosome 20q, was shown to be linked in a single extended family (2). M0DY1 was recently shown to be caused by mutations in the transcription factor hepatocyte nuclear factor-la (HNF4a) (3). MODY2, located on chromosome 7p (4), is caused by mutations in the glucokinase gene (5). MODY3 was mapped to chromosome 12q (6) and is known to be caused by mutations in another transcription factor, HNF-la (7). Although the relative prevalence of these MODY subtypes varies regionally (8-10), families linked to chromosome 12q are the most frequently described. The glucokinase defects in MODY2 interfere with glucose uptake, resulting in hyperglycemia (5). Although the mechanism of hyperglycemia in MODY1 and MODY3 is not yet understood, phenotypic characterization of these families has shown a deficient insulin secretion response to glucose (11-13).We report here the characterization of the MODY3 gene M region and the results of mutation analysis in eight different aturity-onset diabetes of the young (MODY) is a MODY3 families. We show that MODY3 can be caused by a form of NIDDM with a strong genetic basis, number of different mutations in HNF-la including a mutaDiagnostic criteria for MODY include 1) age of tional hotspot. onset <25 years, 2) correction of fasting hyperglycemia without insulin for at least 2 years, 3) nonketotic RESEARCH DESIGN AND METHODS disease, and 4) autOSOmal dominant mode Of inheritance (1). Family ascertainment and linkage analysis. Families were ascertained based It is therefore expected that a Significant proportion Of MODY on the criteria described by Lehto et al. (13). Genomic DNA was isolated from is caused by Single-gene defects. To date, linkage analysis has P eri P heral blood lymphocytes using standard protocols. Genotyping was pershown that three different, dominant-acting loci can cause fo ™ ed t^^ flu0

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Analysis of the glucokinase gene in Mexican families displaying early-onset non-insulin-dependent diabetes mellitus including MODY families

et al. 1997

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Non-insulin-dependent diabetes mellitus (NIDDM) is the most common form of diabetes, affecting 5% of the general population. Genetic factors play an important role in the development of the disease. While in other populations NIDDM is usually diagnosed after the fifth decade of life, in Mexico a large proportion of patients develop the disease at an early age (between the third and the fourth decade). In Caucasian population, mutations in the glucokinase gene, the TCF1, and TCF14 genes, have been identified in a subgroup of early-onset NIDDM patients denominated MODY (maturity-onset diabetes of the young), which show an autosomal dominant pattern of inheritance. As a first step in the molecular characterization of Mexican families displaying early-onset NIDDM we searched for mutations in the glucokinase gene through SSCP analysis and/or direct sequencing in 26 individuals from 22 independent families, where at least four can be classified as MODY. No mutations were detected in the exons or the intron-exon boundaries of the gene in any of the screened individuals. The phenotype and clinical profile of some of the studied patients is compatible with that of patients carrying mutations in the TCF1 or TCF14 genes, while others may carry mutations in different loci. Through computer simulation analysis we identified at least four informative families which will be used for further linkage studies.

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A gene for maturity onset diabetes of the young (MODY) maps to chromosome 12q

Cited by 182 publications

References 12 publications

Contribution of Known and Unknown Susceptibility Genes to Early-Onset Diabetes in Scandinavia

Contribution of Known and Unknown Susceptibility Genes to Early-Onset Diabetes in Scandinavia

Novel Mutations and a Mutational Hotspot in the M0DY3 Gene

Analysis of the glucokinase gene in Mexican families displaying early-onset non-insulin-dependent diabetes mellitus including MODY families

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