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A novel unstable mutation in mitochondrial DNA responsible for maternally inherited diabetes and deafness.

ABSTRACT: OBJECTIVE: The m.3243A>G mutation in mitochondrial DNA (mtDNA) is responsible for maternally inherited diabetes and deafness (MIDD). Other mtDNA mutations are extremely rare. RESEARCH DESIGN AND METHODS: We studied a patient presenting with diabetes and deafness who does not carry the m.3243A>G mutation. RESULTS: We identified a deficiency of respiratory chain complex I in the patient's fibroblasts. mtDNA sequencing revealed a novel mutation that corresponds to an insertion of one or two cytosine residues in the coding region of the MT-ND6 gene (m.14535_14536insC or CC), leading to premature stop codons. This heteroplasmic mutation is unstable in the patient's somatic tissues. CONCLUSIONS: We describe for the first time an unstable mutation in a mitochondrial gene coding for a complex I subunit, which is responsible for the MIDD phenotype. This mutation is likely favored by the m.14530T>C polymorphism, which is homoplasmic and leads to the formation of an 8-bp polyC tract responsible for genetic instability.

SUBMITTER: Bannwarth S

PROVIDER: S-EPMC3220838 | biostudies-other | 2011 Dec

REPOSITORIES: biostudies-other

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A novel unstable mutation in mitochondrial DNA responsible for maternally inherited diabetes and deafness.

Bannwarth Sylvie S Abbassi Meriame M Valéro René R Fragaki Konstantina K Dubois Noémie N Vialettes Bernard B Paquis-Flucklinger Véronique V

Diabetes care 20111012 12

<h4>Objective</h4>The m.3243A>G mutation in mitochondrial DNA (mtDNA) is responsible for maternally inherited diabetes and deafness (MIDD). Other mtDNA mutations are extremely rare.<h4>Research design and methods</h4>We studied a patient presenting with diabetes and deafness who does not carry the m.3243A>G mutation.<h4>Results</h4>We identified a deficiency of respiratory chain complex I in the patient's fibroblasts. mtDNA sequencing revealed a novel mutation that corresponds to an insertion of ...[more]

PMID: 21994425

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Project description:BackgroundNuclear genes or family-based mitochondrial screening have been the focus of genetic studies into essential hypertension. Studies into the role of mitochondria in sporadic Chinese hypertensives are lacking. The objective of the study was to explore the relationship between mitochondrial DNA (mtDNA) variations and the development of maternally inherited essential hypertension (MIEH) in China.MethodsYangzhou residents who were outpatients or in-patients at the Department of Cardiology in Northern Jiangsu People's Hospital (Jiangsu, China) from June 2009 to June 2015 were recruited in a 1:1 case control study of 600 gender-matched Chinese MIEH subjects and controls. Genomic DNA was isolated from whole blood cells. The most likely sites for hypertension were screened using oligodeoxynucleotides at positions 7908-8816, purified and subsequently analyzed by direct sequencing according to the revised consensus Cambridge sequence. The frequency, density, type and conservative evolution of mtDNA variations were comprehensively analyzed.ResultsWe found a statistical difference between the two groups for body mass index, waist circumference, abdominal circumference, triglyceride, low-density lipoprotein cholesterol, fasting blood glucose, uric acid, creatinine and blood urea nitrogen (P < 0.05). More amino-acid changes and RNA variants were found in MIEH subjects than the controls (P < 0.01). The detection system simultaneously identified 40 different heteroplasmic or homoplasmic mutations in 4 genes: COXII, tRNALys, ATP8 and ATP 6. The mtDNA variations were mainly distributed in regions of ATP6 binding sites, and the site of highest mutation frequency was m. 8414C > T. Three changes in single bases (C8414T in ATP8, A8701G in ATP6 and G8584A in ATP6) were significantly different in the MIEH patients and the controls (P < 0.001). The m.8273_8281del mutation was identified from 59 MIEH patients.ConclusionsOur results indicate that novel mtDNA mutations may be involved in the pathological process of MIEH, and mitochondrial genetic characteristics were identified in MIEH individuals.

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A novel unstable mutation in mitochondrial DNA responsible for maternally inherited diabetes and deafness.

Publications

A novel unstable mutation in mitochondrial DNA responsible for maternally inherited diabetes and deafness.

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