High frequency of mutations in MODY and mitochondrial genes in Scandinavian patients with familial early-onset diabetes

Lehto, Markku; Wipemo, C; Ivarsson, Sten-Anders; Lindgren, Cecilia M.; Lipsanen‐Nyman, Marita; Weng, Jianping; Wibell, L; Widén, Elisabeth; Tuomi, Tiinamaija; Groop, Leif

doi:10.1007/s001250051281

Cited by 116 publications

(91 citation statements)

References 16 publications

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“…In addition, we screened them for mutations in known MODY genes, the A3243G mitochondrial DNA mutation, and presence of GADA and type 1 diabetes HLA risk alleles DQB*02 and/or 0302. The frequency of MODY/MIDD mutations in this study is higher than we have previously published (20). This is not an unexpected finding, as we selected large families with diabetes in several generations.…”

Section: Discussionsupporting

confidence: 49%

“…Of them, 13% had mutations in MODY or mitochondrial genes (20), indicating that there are underlying genetic causes left to be found in families with EOD. To unravel some of the unknown genetic background of EOD, we performed a genome-wide scan in 29 pedigrees including 119 affected subjects.…”

Section: Discussionmentioning

confidence: 99%

“…The A3243G mitochondrial DNA mutation was found to segregate with diabetes and hearing loss in one family (20). In the three families in which MODY/MIDD mutations segregated with disease, four subjects (31%) had an initial diagnosis of type 1 diabetes, eight (62%) subjects had a diagnosis of type 2 diabetes, and one (7%) subject had a diagnosis of IGT (Table 1).…”

Section: Screening For Mody and Midd Mutationsmentioning

confidence: 99%

“…Of the 29 screened families, 7 (24%) were found to have either MODY or MIDD mutations. In two families, mutations (R131Q and L107I) in the HNF-1␣ gene (MODY3) segregated completely with diabetes, and both variants have been shown to be functional (20). Mutations in the IPF-1 gene (MODY4) were found in patients from three families, two of which had the P239Q and one of which had the G212R variant (28).…”

Section: Screening For Mody and Midd Mutationsmentioning

confidence: 99%

“…In addition to locus heterogeneity, substantial allelic heterogeneity has been found in the different MODY loci, and Ͼ50 different mutations have been identified in both the HNF-1␣ and the GCK genes (3,5). Between 11 and 45% of families that fulfill MODY criteria do not have mutations in known MODY genes (MODYX) (3,8,(17)(18)(19)(20).…”

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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: Discussionsupporting

confidence: 49%

Section: Discussionmentioning

confidence: 99%

Section: Screening For Mody and Midd Mutationsmentioning

confidence: 99%

Section: Screening For Mody and Midd Mutationsmentioning

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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Macular Dystrophy Associated With the A3243G Mitochondrial DNA Mutation

Michaelides

Jenkins²,

Bamiou³

et al. 2008

Arch Ophthalmol

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Objectives: To determine (1) detailed retinal and audiological features of probands harboring the A3243G mitochondrial DNA mutation (m.3243AϾG) and their asymptomatic maternal relatives, (2) intrafamilial and interfamilial phenotypic variability, and (3) the presence of other systemic features. Methods: Seven probands harboring the A3243G mitochondrial DNA mutation and 36 asymptomatic maternal relatives were ascertained. Participants underwent ophthalmologic examination, fundus photography, autofluorescence imaging, and audiological evaluation and completed a questionnaire. Blood samples were taken to test for diabetes, determine renal function, and screen relatives for the A3243G mutation. Results: The A3243G mutation was associated with both intrafamilial and interfamilial variable expressivity regarding retinal appearance, hearing loss, diabetes, and other systemic features. The most common macular appearance in maternal relatives (one-third of those positive for the mutation) was mild abnormalities of the retinal pigment epithelium (more clearly identified using autofluorescence), which may therefore be a useful clinical indicator suggesting positive mutation status. Four probands and 13 mutation-positive relatives were found to have evidence of significant bilateral, cochlear, symmetrical age-adjusted hearing loss, predominantly affecting high frequencies. Conclusions: Hearing loss and macular disturbance were the most frequent findings in mutation-positive participants, with 95% of mutation-positive relatives having hearing loss. Diabetes was the least frequent finding. Patients with progressive hearing loss may merit ophthalmologic assessment to detect retinal abnormalities consistent with the A3243G mutation. Conversely, patients with macular features in keeping with the A3243G mutation should have audiological testing, even in the absence of diabetes or a positive family history.

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Hepatocyte nuclear factor 1 alpha (HNF-1?) mutations in maturity-onset diabetes of the young

Ellard

2000

Hum. Mutat.

106

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High frequency of mutations in MODY and mitochondrial genes in Scandinavian patients with familial early-onset diabetes

Cited by 116 publications

References 16 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

Macular Dystrophy Associated With the A3243G Mitochondrial DNA Mutation

Hepatocyte nuclear factor 1 alpha (HNF-1?) mutations in maturity-onset diabetes of the young

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