The first concurrent detection of mitochondrial DNA m.3243A>G mutation, deletion, and depletion in a family with mitochondrial diabetes

Abstract

BackgroundMitochondrial diabetes (MD) is a rare monogenic form of diabetes and divided into type l and type 2. It is characterized by a strong familial clustering of diabetes with the presence of maternal transmission in conjunction with bilateral hearing impairment in most of the carriers. The most common form of MD is associated with the m.3243A>G mutation in the mitochondrial MT‐TL1, but there are also association with a range of other point mutations, deletion, and depletion in mtDNA.MethodsThe mitochondrial genome anomalies were investigated in a family with clinical features of MD, which includes a proband presenting severe MD conditions including cardiomyopathy, retinopathy, and psychomotor retardation.ResultsBy investigating the patient's blood leukocytes and skeletal muscle, we identified the m.3243A>G mutation in heteroplasmic state. This mutation was absent in the rest of the family members. In addition, our analysis revealed in the proband a large mtDNA heteroplasmic deletion (~1 kb) and a reduction in mtDNA copy number.ConclusionOur study points out, for the first time, a severe phenotypic expression of the m.3243A>G point mutation in association with mtDNA deletion and depletion in MD.

The clinical and genetic characteristics of maternally inherited diabetes and deafness (MIDD) with mitochondrial m.3243A > G mutation: A 10‐year follow‐up observation study and literature review

“…Most patients have normal or lean body mass, with an average BMI of less than 20 kg/m 2 4 . Most patients have negative results for islet autoantibodies 5 . Abnormalities in glucose metabolism associated with multiorgan damage.…”

“…4 Most patients have negative results for islet autoantibodies. 5 Abnormalities in glucose metabolism associated with multiorgan damage. Special attention should be paid to patients with early-onset diabetic retinopathy.…”

“…Since then, a growing body of scientific evidence suggests that a range of other point mutations in the mtDNA may also contribute to the pathogenesis of MIDD, such as mt‐tRNA encoding genes, including MT‐TI, MT‐TS1, and MT‐TK, and mt‐proteins encoding genes, including MT‐ND1, MT‐ND4, MT‐COX2, and MT‐COX3. In addition, nucleotide deletions and depletions have also been described in patients with MIDD 5 . However, these novel mutations are extremely rare compared to the mt.3243A > G. MIDD is considered to be the most common type of monogenic diabetes mellitus, accounting for about 1% of all diabetes mellitus, and its incidence in China is approximately 0.6% 6 …”

“…In addition, nucleotide deletions and depletions have also been described in patients with MIDD. 5 However, these novel mutations are extremely rare compared to the mt.3243A > G. MIDD is considered to be the most common type of monogenic diabetes mellitus, accounting for about 1% of all diabetes mellitus, and its incidence in China is approximately 0.6%. 6 Due to its low incidence and heterogeneous clinical presentation, MIDD is often misdiagnosed as type 1 or type 2 diabetes.…”

Identification of a Novel Mitochondrial tRNA Mutation in Chinese Family with Type 2 Diabetes Mellitus

“…5–8 In particular, the well-known m.A3243G mutation in tRNA Leu(UUR) was implicated in the pathogenesis and progression of T2DM in many families worldwide. 9–11 This mutation affected the structural stability, aminoacylation rate and post-transcriptional modification of tRNA Leu(UUR) . 12 In addition to the m.A3243G mutation, some case–control studies suggested that tRNA Trp A5514G and tRNA Ser(AGY) C12337T, 13 tRNA Glu A14692G, 14 tRNA Ala T5587C and ND5 T12338C 15 mutations were associated with T2DM.…”