Comparison of mitochondrial A3243G mutation loads in easily accessible samples from a family with maternally inherited diabetes and deafness

Abstract

Abstract. The mitochondrial A3243G mutation is most commonly related to the MELAS syndrome, but can cause many different clinical manifestations at various ages. Here, we present a family with maternally inherited diabetes and deafness (MIDD), the proband of which exhibits hearing loss, diabetes mellitus, cardiomyopathy and short stature. Four easily accessible samples (whole blood, hair roots, buccal scrapings and urinary sediment) from the proband and her 3 sons were simultaneously analyzed for heteroplasmic percentages of the A3243G mutation in their DNA. More than 10 subclones were sequenced and the percentage of clones possessing the A3243G mutation was calculated. The proportion of mutant genomes varied widely among the four samples tested. Blood DNA consistently had the lowest percentage of mutation load, while urinary sediment tended to have the highest. The 3 sons have not exhibited hearing disability or diabetes mellitus thus far. However, their mutation loads in all 4 tissue samples were higher than those in the corresponding samples from the proband. Follow-up of this family over time is necessary to understand the relationship between the heteroplasmic mutation loads in the 4 different samples and the clinical manifestations of MIDD/MELAS.

The Mutations and Clinical Variability in Maternally Inherited Diabetes and Deafness: An Analysis of 161 Patients

“…DNA from urothelium, myocardium, and buccal mucosa had the higher while blood had the lowest proportion of mutant genomes. These results are consistent with a previous research ( 20 ). Each time a somatic cell undergoes mitosis, mtDNA will be randomly distributed to the progeny cells along with mitochondria.…”

“…Further, ragged red fibers on muscle biopsy are typically seen in MIDD, which indicate damaged muscles and are thought to be pathognomonic of mitochondrial disease ( 19 ). Muscle biopsy may show ragged-red fibers that are characteristic of mitochondrial disorders and contribute to the diagnosis of MIDD ( 20 ).…”

“…Cardiac conductance disorders might occur by a rearrangement of the cardiac conductance system induced by the mitochondrial dysfunction. Common cardiac conduction abnormalities seen in MIDD include Wolff Parkinson White syndrome, frequent ventricular extrasystoles, and atrial fibrillation ( 20 , 22 ). Cardiac conductance disorders might contribute to sudden deaths; therefore, patients diagnosed with MIDD should undergo a comprehensive cardiac examination to avoid adverse outcomes ( 15 ).…”

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

“…[5][6][7][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][10][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.…”