Molecular and Clinical Characterization of the Variable Phenotype in Korean Families with Hearing Loss Associated with the Mitochondrial A1555G Mutation

Abstract

Hearing loss, which is genetically heterogeneous, can be caused by mutations in the mitochondrial DNA (mtDNA). The A1555G mutation of the 12S ribosomal RNA (rRNA) gene in the mtDNA has been associated with both aminoglycoside-induced and non-syndromic hearing loss in many ethnic populations. Here, we report for the first time the clinical and genetic characterization of nine Korean pedigrees with aminoglycoside-induced and non-syndromic hearing loss. These Korean families carry in the A1555G mutation of 12S rRNA gene and exhibit variable penetrance and expressivity of hearing loss. Specifically, the penetrance of hearing loss in these families ranged between 28.6% and 75%, with an average of 60.8%. These results were higher than the 29.8% penetrance that was previously reported in a Chinese population but similar to the 65.4% and 54.1% penetrance observed in a large Arab-Israeli population and nineteen Spanish pedigrees, respectively. The mutational analysis of the complete mtDNA genome in these families showed that the haplogroups of the Korean population, which belongs to the eastern Asian population, were similar to those of the Chinese population but different from the Spanish population, which belongs to the European-Caucasian population. The mtDNA variants that may act as modifier factors were also found to be similar to the Chinese population. Although the mtDNA haplogroups and variants were similar to the eastern Asian population, we did find some differing phenotypes, although some subjects had the same variants. This result suggests that both the ethnic background and environmental factors lead to a variable phenotype of the A1555G mutation.

A Rapid Method for Simultaneous Screening of Multi-Gene Mutations Associated with Hearing Loss in the Korean Population

“…Based on previous genetic studies of HL in the Korean population, we selected the seven most common mutations that lead to hereditary HL [8]–[12], [31]. Multiplex genotyping of these seven mutations was successfully performed using SNaPshot minisequencing, which produced accurate data and a detection rate of the mutations that was found to account for up to 40% of the causative mutant alleles associated with prelingual HL in Koreans [8].…”

“…Mitochondrial DNA mutations have also been reported in both nonsyndromic and syndromic HL. Among these mutations, only the m.1555A>G mutation of the MT-RNR1 gene (OMIM 561000) has been identified repeatedly in Koreans with HL by our previous studies [11], [12]. Based on the prevalence of mutations from the previous studies, we selected 7 mutations which show the high frequencies in Korean hearing loss population and designed the method to detect effectively mutant alleles through rapid screening: c.235delC of GJB2 , c.919-2A>G and c.2168A>G of SLC26A4 and m.1555A>G of the MT-RNR1 gene.…”

Prevalence of Mutations in GJB2, SLC26A4, and mtDNA in Children with Severe or Profound Sensorineural Hearing Loss in Southwestern China

“…The primers for both genes were the same as previously reported (Bae et al, 2012). Amplified DNA fragments were purified with a gel extraction kit (Qiagen) and then sequenced by the ABI 377 sequencer.…”

The mitochondrial transfer RNAAsp A7551G mutation may contribute to the clinical expression of deafness associated with the A1555G mutation in a pedigree with hearing impairment

“…Of the mutations in human mtDNA, A1555G is one of the most common pathogenic mutations associated with aminoglycoside ototoxicity (6). However, increasing evidence has shown that the A1555G mutation cannot directly lead to hearing loss, as among pedigrees with maternally inherited deafness, a certain number of members (despite carrying the A1555G mutation) exhibit different levels of hearing, ranging from normal to profound hearing loss (7)(8)(9)(10)(11). Therefore, aminoglycosides, nuclear-encoded genes and the mtDNA genetic background may actively function in the occurrence of deafness (12,13).…”