Increased variation in mtDNA in patients with familial sensorineural hearing impairment

Abstract

Analyses of mitochondrial DNA (mtDNA) sequences have revealed non-neutral patterns, suggesting that many amino acid mutations in animal mtDNA may be mildly deleterious, but this has not been verified in human clinical series. Since sensorineural hearing impairment (SNHI) is a common manifestation in many of the syndromes caused by mutations in mtDNA, this may be regarded as the phenotype of choice in attempts to detect mutations that may have a mildly deleterious effect on mitochondrial function. We selected 32 subjects from among 117 unrelated SNHI patients with SNHI in maternal relatives by means of family history, determined the entire coding region sequence of mtDNA and compared the sequence variation with that in 32 haplogroup-matched controls taken at random from 192 Finnish sequences. The 32 control sequences differed from the remaining 160 sequences by 36+/-9 substitutions (mean +/- SD), while the difference for the 32 patients was 58+/-4 substitutions ( P=0.005 for difference; Wilcoxon signed rank test). Differences were also found in the number of new haplotypes and new non-synonymous mutations or mutations in tRNA or rRNA genes. A total of 12 rare mtDNA variants were detected in the patients, and only 3 of these were considered to be neutral in effect. It is proposed that increased sequence variation in mtDNA may be a genetic risk factor for SNHI, and the increased frequency of rare haplotypes in these patients points to the presence of mildly deleterious mutations in mtDNA.

Prevalence of 15 mitochondrial DNA mutations among type 2 diabetic patients with or without clinical characteristics of maternally inherited diabetes and deafness

“…This last patient also presented ischemic cardiomyopathy, nonproliferative diabetic retinopathy and cataract. The C8393T mutation in the ATPase8 gene was previously described in subjects with LHON syndrome or neurosensorial deafness (24,25). This mutation was observed in two "classical" type 2 diabetic patients and in one patient of the MIDD group.…”

Mitochondrial DNA mutations in patients with postlingual, nonsyndromic hearing impairment

“…An increased number of rare polymorphisms has been reported among Finnish patients with sensorineural hearing impairment, compared with controls, consistent with at least some of them being mildly deleterious mutations contributing collectively to the phenotype. 44 The mtDNA polymorphisms reported here should be considered as possible candidates for involvement in hearing disorders, but there is at this time no compelling evidence to support any.…”

Mitochondrial Genetic Background Modifies Breast Cancer Risk

“…Pathogenic expression of homoplasmic mtDNA mutations may also need a complex nuclear-mitochondrial interaction (8). Studies have suggested that mtDNA polymorphisms are associated with a variety of disorders, including Alzheimer's disease (9), acute myocardial infarction (10), bipolar disorder (11), Leber's hereditary optic neuropathy (6,12), sensorineural hearing impairment (13,14), Parkinson's disease (15)(16)(17)(18), stroke (19,20), and Wolfram (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) syndrome (21,22). Most of these studies focused on one or limited number of mtDNA single-nucleotide polymorphisms (SNP).…”