Extensive and rapid screening for major mitochondrial DNA point mutations in patients with hereditary hearing loss

Abstract

Sensorineural hearing loss (HL) is one of the most frequent clinical features in patients with mitochondrial diseases caused by mitochondrial DNA (mtDNA) mutations, and hearing is impaired in over half of all cases with mitochondrial disorders. This study analyzed 373 patients with suspected hereditary HL using an extensive and rapid suspension-array screening system for 29 major mtDNA mutations, including the m.1555A4G homoplasmic mutation in the MT-RNR1 gene, which causes non-syndromic sensorineural HL and aminoglycoside-induced HL, and the m.3243A4G heteroplasmic mutation in the MT-TL1 gene. This method is rapid and suitable for large-scale screening because universal 96-well plates are available for use, and because an analysis of each plate can be completed within 1 h. This system detected five different mtDNA mutations in 24 of the 373 (6.4%) patients. The m.1555A4G and m.3243A4G mutations were detected in 11 (2.9%) and 9 (2.7%) patients, respectively. In addition, three mutations, that is, m.8348A4G in the MT-TK gene, m.11778G4A in the MT-ND4 gene and 15498G4A in the MT-CYB gene were detected in one patient for each. This screening system is useful for the genetic diagnosis and epidemiological study of both syndromic and non-syndromic HL.

Postlingual Hearing Loss as a Mitochondrial 3243A>G Mutation Phenotype

“…This figure is lower than ∼2.4% reported for Japanese HI patients [20], [31], [32], but similar to that reported in a diabetic Caucasian cohort [33] and 3 times less than the prevalence of m.1555A>G mutation (3.4%) reported for HL patients [34]. A similar hearing loss study was carried out by Majamaa et al who found m.3243A>G mutation in 2.1% of 250 HL patients by applying pre-selection based on maternal inheritance [16].…”

Mitochondrial DNA haplogroup associated with hereditary hearing loss in a Japanese population

“…These patients were suspected of having hereditary HL because they had a family history of it or because they had no other apparent cause of HL. We had previously detected the m.1555A>G and the m.3243A>G mutations in a total of 20 of these patients [7]. Because these mutations are located in mtDNA and thought to contribute strongly to the phenotypic expression of HL, we excluded these 20 patients from the case-control analysis.…”

“…The patients had visited the outpatient clinic of the Department of Otolaryngology, University Hospital of Medicine, Tokyo Medical and Dental University. Background characteristics of these patients are shown in Table I and were described previously [7]. These patients were suspected of having hereditary HL because they had a family history of it or because they had no other apparent cause of HL.…”

“…In fact, previous studies have revealed that HL is correlated with genetic polymorphisms in somatic genes [3,4]. Many pathogenic mitochondrial DNA (mtDNA) mutations are well known to cause HL [5][6][7]. Just as in the case of genetic polymorphisms in somatic genes, it is natural to consider that mtDNA polymorphisms could be associated with the phenotypic expression of HL.…”

Extended screening for major mitochondrial DNA point mutations in patients with hereditary hearing loss

“…4 Our previous survey of 373 patients with suspected HL by use of this screening system revealed the m.1555A4G mutation in 11 patients, the m.3243A4G mutation in 9 patients, and the m.8348A4G, m.11778G4A and m.15498G4A mutations in 1 patient each. In the present extended study, we increased the number of mutations that could be detected from 29 to 61.…”