Abstract
Background The syndrome of maternally inherited diabetes and deafness (MIDD) is typically caused by the m.3243A>G mutation and widely considered maternally inherited. In our study, we aimed to investigate the heredity way of the m.3243A>G among pedigrees with MIDD and discover novel mitochondrial DNA mutations related to atypical clinical phenotypes. Methods Heteroplasmy levels of the m.3243A>G mutation in peripheral blood, saliva, and urine sediment of 31 individuals from 10 unrelated pedigrees were measured by pyrosequencing. Clinical evaluations including endocrinological, audiological, and magnetic resonance imaging (MRI) examinations, mitochondrial function evaluation in peripheral blood mononuclear cells (PBMCs), and whole mitochondrial DNA (mtDNA) sequencing were performed among the spontaneous mutant pedigrees. Results Among the 10 unrelated MIDD pedigrees, we found that the de novo m.3243A>G mutation occurred in the family 1957 (F1957). The proband (F1957-II-1) and her son (F1957-III-1) both manifested diabetes with mild bilateral sensorineural hearing loss (SNHL) and abnormal brain MRI, and F1957-III-1 also complained of severe nausea and vomiting. Mitochondrial function evaluation in PBMCs revealed an increased level of ROS generation and decreased levels of ATP and mitochondrial membrane potential (ΔΨm) in the two m.3243A>G carriers. Whole mtDNA sequencing also revealed a de novo heteroplasmic substitution at m.16093T>C in both the proband and her son. Conclusions Our study showed that de novo m.3243A>G mutation accompanied by other point mutations may occur in the very early embryonic or germ cell stage without maternal inheritance, bringing about both typical and atypical clinical features.
Highlights
The syndrome of maternally inherited diabetes and deafness (MIDD) is largely caused by an A-to-G transition at position3243 of mitochondrial DNA tRNALeu-encoding (UUR) gene, which is one of the most common point mutations of mtDNA [1]
To determine whether the capacity of oxidative phosphorylation in peripheral blood mononuclear cells (PBMCs) varies among family members, the levels of cellular and mitochondrial ATP were measured by a luciferin/ luciferase assay
We used pyrosequencing to analyze the heteroplasmy levels of the m.3243A>G mutation in peripheral blood, saliva, and urine sediment, which enabled the ROS generation (% of controls) Mitochondrial membrane potential ATP production (% of controls)
Summary
The syndrome of maternally inherited diabetes and deafness (MIDD) is typically caused by the m.3243A>G mutation and widely considered maternally inherited. We aimed to investigate the heredity way of the m.3243A>G among pedigrees with MIDD and discover novel mitochondrial DNA mutations related to atypical clinical phenotypes. Audiological, and magnetic resonance imaging (MRI) examinations, mitochondrial function evaluation in peripheral blood mononuclear cells (PBMCs), and whole mitochondrial DNA (mtDNA) sequencing were performed among the spontaneous mutant pedigrees. Among the 10 unrelated MIDD pedigrees, we found that the de novo m.3243A>G mutation occurred in the family 1957 (F1957). Whole mtDNA sequencing revealed a de novo heteroplasmic substitution at m.16093T>C in both the proband and her son. Our study showed that de novo m.3243A>G mutation accompanied by other point mutations may occur in the very early embryonic or germ cell stage without maternal inheritance, bringing about both typical and atypical clinical features
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