Defining the Importance of Mitochondrial Gene Defects in Maternally Inherited Diabetes by Sequencing the Entire Mitochondrial Genome

Choo-Kang, Alan T.W.; Lynn, Stephen; Taylor, Geoffrey A.; Daly, Mark E.; Sihota, Sarbpreet S.; Wardell, Teressa M.; Chinnery, Patrick F.; Turnbull, Douglass M.; Walker, Mark S.

doi:10.2337/diabetes.51.7.2317

Cited by 32 publications

(19 citation statements)

References 13 publications

(10 reference statements)

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“…As mentioned above, the genetic analysis of MIDD usually focuses on the search for the 3243A>G mutation in selected diabetic patients affected by hearing loss; the entire mitochondrial genome is rarely screened [29], [30]. Sequence analysis of the whole mtDNA in our suspected mitochondrial diabetic pediatric patients and controls resulted in a high rate of mtDNA polymorphisms (a total of 383/416 variants, present also in controls).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Diabetes in Children: Seek and You Will Find It

et al. 2012

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Maternally Inherited Diabetes and Deafness (MIDD) is a rare form of diabetes due to defects in mitochondrial DNA (mtDNA). 3243 A>G is the mutation most frequently associated with this condition, but other mtDNA variants have been linked with a diabetic phenotype suggestive of MIDD. From 1989 to 2009, we clinically diagnosed mitochondrial diabetes in 11 diabetic children. Diagnosis was based on the presence of one or more of the following criteria: 1) maculopathy; 2) hearing impairment; 3) maternal heritability of diabetes/impaired fasting glucose and/or hearing impairment and/or maculopathy in three consecutive generations (or in two generations if 2 or 3 members of a family were affected). We sequenced the mtDNA in the 11 probands, in their mothers and in 80 controls. We identified 33 diabetes-suspected mutations, 1/33 was 3243A>G. Most patients (91%) and their mothers had mutations in complex I and/or IV of the respiratory chain. We measured the activity of these two enzymes and found that they were less active in mutated patients and their mothers than in the healthy control pool. The prevalence of hearing loss (36% vs 75–98%) and macular dystrophy (54% vs 86%) was lower in our mitochondrial diabetic adolescents than reported in adults. Moreover, we found a hitherto unknown association between mitochondrial diabetes and celiac disease. In conclusion, mitochondrial diabetes should be considered a complex syndrome with several phenotypic variants. Moreover, deafness is not an essential component of the disease in children. The whole mtDNA should be screened because the 3243A>G variant is not as frequent in children as in adults. In fact, 91% of our patients were mutated in the complex I and/or IV genes. The enzymatic assay may be a useful tool with which to confirm the pathogenic significance of detected variants.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial Diabetes in Children: Seek and You Will Find It

et al. 2012

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“…Among these methods, direct sequencing is the gold-standard for systemic examination of mutation and for novel mutation detection (Choo-Kang et al 2002). In our study, we sequenced the entire mtDNA genome.…”

Section: Discussionmentioning

confidence: 99%

Novel Mutations of Mitochondrial DNA Associated with Type 2 Diabetes in Chinese Han Population

Liao

Pang

et al. 2008

Tohoku J. Exp. Med.

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Mitochondrial single nucleotide polymorphisms (mtSNPs) have been reported to associate with type-2 diabetes mellitus (T2DM), but mtSNPs appear to be considerably different among different populations and regions. To determine mtSNPs in Chinese Han patients with T2DM, the entire sequences of the mitochondrial genomes from 72 T2DM Chinese (59 ± 4 years) and 50 age-matched healthy subjects (controls) in Chongqing region of Western China were directly sequenced and mtSNPs were analyzed. We found that M8, M9, D, G, R and A haplogroups exist in Chinese Han population and the frequency of haplogroup M9 was significantly higher in patients with T2DM than in the controls ( p = 0.0006, OR 0.06 [95% CI 0.008-0.476]). MtSNPs T3394C in NADH dehydrogenase subunit 1 (ND1), G4491A in ND2, T16189C and T16519C were found with significantly higher frequency in patients with T2DM than in the controls (T16189C, p = 0.0045; T16519C, p < 0.0001; T3394C, p = 0.0015; G4491A, p = 0.0015). In contrast, the frequency of C5178A in ND2 and A10398G in ND3 was higher in the controls than in patients with T2DM (C5178A, p = 0.014; A10398G, p = 0.0011). Our results indicate that mtSNPs T3394C, G4491A, T16189C and T16519C show susceptible tendency to T2DM and mtSNPs C5178A and A10398G seem to be genetic factors for against T2DM. These mtSNPs determined in our study is useful and could be used for early diagnosis and prevention of T2DM in Chinese Han population.type-2 diabetes mellitus; mitochondrial genome; single nucleotide polymorphisms; haplogroup; Chinese.Tohoku

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“…The criteria of inclusion in the MIDD group were clear evidence of maternal transmission of type 2 DM (presence of DM in the mother and/or other maternal relatives in three consecutive generations or through two consecutive generations with at least three affected individuals) plus two or more of the following features: neurosensorial deafness; age at onset < 40 years; body mass index (BMI) < 25 kg/m 2 ; short stature (< 1.5m for women and < 1.6m for men); low levels of C-peptide and/or use of insulin therapy; and presence of some previously diagnosed mitochondrial disorder, for example, MELAS; neurosensorial deafness; mitochondrial myopathy and myoclonus epilepsy with ragged red fi bers (MERRF); encephalomyopathy; hypertrophic cardiomyopathy; and Leber's hereditary optic neuropathy (LHON) syndrome (1,10).…”

Section: Pacientsmentioning

confidence: 99%

Prevalence of 15 mitochondrial DNA mutations among type 2 diabetic patients with or without clinical characteristics of maternally inherited diabetes and deafness

Crispim

Estivalet

Roisenberg

et al. 2008

Arq Bras Endocrinol Metab

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The aim of the present study is to investigate the prevalence of ten described mitochondrial DNA (mtDNA) mutations in patients with type 2 diabetes, and search for new mutations in four mtDNA genes in a subgroup of patients with characteristics of maternally inherited diabetes and deafness (MIDD). These mutations were investigated in 407 type 2 diabetic patients without characteristics of mitochondrial diabetes ("classical" type 2 diabetes group) and in 38 type 2 diabetic patients with characteristics suggestive of MIDD. Through sequencing of four mtDNA genes in MIDD patients, we selected fi ve others potentially pathogenic mutations that were also screened in the remaining patients. Overall, the frequency of the fi fteen analyzed mutations was 36.84% in the MIDD group and 2.45% in the "classical" type 2 diabetes group (p < 0.001). In conclusion, our study reinforces the importance of mtDNA mutations in the pathogenesis of MIDD.

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Defining the Importance of Mitochondrial Gene Defects in Maternally Inherited Diabetes by Sequencing the Entire Mitochondrial Genome

Cited by 32 publications

References 13 publications

Mitochondrial Diabetes in Children: Seek and You Will Find It

Mitochondrial Diabetes in Children: Seek and You Will Find It

Novel Mutations of Mitochondrial DNA Associated with Type 2 Diabetes in Chinese Han Population

Prevalence of 15 mitochondrial DNA mutations among type 2 diabetic patients with or without clinical characteristics of maternally inherited diabetes and deafness

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