[Modifier factors influencing the phenotypic manifestation of the deafness associated mitochondrial DNA mutations].

Mutations in the mitochondrial DNA have been found to be one of the most important causes of sensorineural hearing loss. In particular, these mutations often occur in the mitochondrial 12S rRNA and tRNA genes. Of these, the homoplasmic A1555G and C1494T mutations in the 12S rRNA have been associated with both aminoglycoside induced and nonsyndromic hearing impairment in many families worldwide. Children carrying the A1555G or C1494T mutation are susceptible to the exposure of ototoxic drugs, thereby inducing or worsening hearing loss. Individuals harboring A1555G or C1494T mutation can also develop hearing loss even in the absence of aminoglycoside exposure. However, matrilineal relatives of intra-families or inter-families carrying the A1555G or C1494T mutation exhibit a wide range of severity, age-at-onset, and audiometric configuration of hearing impairment. These indicate that the A1555G or C1494T mutation is a primary factor underlying the development of deafness but insufficient to produce the clinical phenotype.Thus, other modifier factors, such as aminoglycoside(s), mitochondria l DNA haplotype(s) or nuclear modifier gene(s), play a role in the phenotypic expression of the deafness-associated mitochondrial 12S rRNA A1555G or C1494T mutation. In this review, we summarize the modifier factors for the phenotypic expression of deafness-associated 12S rRNA A1555G and C1494T mutations and propose the molecular pathogenetic mechanism of maternally inherited deafness.

[Hearing loss and epilepsy may be associated with the novel mitochondrial tRNASer(UCN) 7472delC mutation in a Chinese family].

Mutations in mitochondrial DNA have been associated with a wide spectrum of clinical abnormalities. We reported here the clinical and genetic evaluations as well as mutational analysis of mitochondrial DNA(mtDNA) in a three-generation Chinese Han family with maternally transmitted hearing loss and epilepsy. Of 14 matrilineal relatives, three suffered from hearing loss, three had epilepsy, and other did not have significant clinical abnormalities. Sequence analysis of mitochondrial genome in this family identified the novel 7472delC in tRNASer(UCN) and 33 variants belonging to Asian haplogroup B4b1a2. The 7472delC locates at the highly conserved residue of T-arm of this tRNA. In fact, the 7472insC at the same position of this tRNA has been associated with hearing loss and epilepsy in several genetically unrelated families. The 7472insC has been shown to lead to a failure in tRNA metabolism and mitochondrial dysfunction. Thus, 7472delC mutation, similar to 7472insC mutation, may result in the mitochondrial dysfunctions responsible for the hearing loss and epilepsy. Furthermore, none of mutation in deafness-associated GJB2 gene was detected in this Chinese family. Therefore, the 7472delC is likely a new mitochondrial mutation with hearing loss and epilepsy.

[Mitochondrial DNA G7444A mutation may influence the phenotypic manifestation of the deafness-associated 12S rRNA A1555G mutation].

Mitochondrial 12S rRNA and tRNASer(UCN) genes are the hot spots for mutations associated with hearing loss. We reported here the clinical, genetic and molecular analysis of a Chinese pedigree with maternally inherited sensorineural hearing loss. Molecular analysis showed that the pedigree carried both mitochondrial DNA (mtDNA) A1555G and G7444A mutations. The penetrance of hearing loss in this pedigree was 58% when aminoglycoside-induced hearing loss was included. When the effect of aminoglycosides was excluded, the penetrance of hearing loss in this pedigree was 25%. The penetrance of hearing loss was significantly higher than other families carrying only A1555G mutation. Sequence analysis of the complete mitochondrial genome in the proband showed that there were 28 mtDNA polymorphisms belonging to East-Asian haplogroup B4c1. In addition to the deafness-associated A1555G and G7444A mutations, there were no other functionally significant variants found in this family. This indicated that mtDNA G7444A mutation may aggravate mitochondrial dysfunction associated with the A1555G mutation. Therefore, the coexistence of both mtDNA mutations may contribute to high penetrance of hearing loss.