Abstract
BackgroundThe genetic background of type 2 diabetes is complex involving contribution by both nuclear and mitochondrial genes. There is an excess of maternal inheritance in patients with type 2 diabetes and, furthermore, diabetes is a common symptom in patients with mutations in mitochondrial DNA (mtDNA). Polymorphisms in mtDNA have been reported to act as risk factors in several complex diseases.FindingsWe examined the nucleotide variation in complete mtDNA sequences of 64 Finnish patients with matrilineal diabetes. We used conformation sensitive gel electrophoresis and sequencing to detect sequence variation. We analysed the pathogenic potential of nonsynonymous variants detected in the sequences and examined the role of the m.16189 T>C variant. Controls consisted of non-diabetic subjects ascertained in the same population. The frequency of mtDNA haplogroup V was 3-fold higher in patients with diabetes. Patients harboured many nonsynonymous mtDNA substitutions that were predicted to be possibly or probably damaging. Furthermore, a novel m.13762 T>G in MTND5 leading to p.Ser476Ala and several rare mtDNA variants were found. Haplogroup H1b harbouring m.16189 T > C and m.3010 G > A was found to be more frequent in patients with diabetes than in controls.ConclusionsMildly deleterious nonsynonymous mtDNA variants and rare population-specific haplotypes constitute genetic risk factors for maternally inherited diabetes.
Highlights
The genetic background of type 2 diabetes is complex involving contribution by both nuclear and mitochondrial genes
We discovered one patient belonging to haplogroup R1a, which is rare in the Finnish population
Certain mitochondrial DNA (mtDNA) haplotypes considered to be Saami specific are found in the Finnish population suggesting a genetic admixture, which appears to be more pronounced in northern Finland
Summary
The genetic background of type 2 diabetes is complex involving contribution by both nuclear and mitochondrial genes. Mitochondrial oxidative phosphorylation (OXPHOS) produces adenosine triphosphate (ATP) that is the energy form driving cellular processes Both nuclear genome and mitochondrial DNA (mtDNA) code for the subunits of the respiratory chain complexes that catalyse the reactions of OXPHOS. Inherited mtDNA consists of 16 569 base pairs and codes for 13 proteins of the respiratory chain, while the remaining more than 70 subunits are encoded by the nuclear genome. It has been postulated that certain mtDNA polymorphisms either decrease or increase the patency of the mitochondrial respiratory chain and the production of harmful ROS. Amino acid variation in subunits of complexes can have minor effects on the stability and assembly of the supercomplexes and may lead to impaired function of OXPHOS or increased ROS production [5,6]
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