Maternally inherited nonsyndromic hearing loss

Abstract

In this study we characterized clinically and evaluated molecularly a large family with maternally inherited hearing impairment. Relatives were evaluated audiologically and clinically, the most likely pattern of inheritance was deduced, and molecular DNA analysis for the known mitochondrial mutations associated with hearing impairment was performed. Clinical examination of several relatives showed a normal general state of health, but in 14 of the members tested variable degrees of sensorineural hearing loss were noted. The pedigree was established and demonstrated a clear pattern of maternal inheritance, with 34 of 38 offspring of deaf mothers being hearing impaired, but none of 22 offspring of deaf fathers having any hearing impairment. Since by far the most likely explanation of such a maternal inheritance pattern is a mitochondrial mutation, molecular testing for the three known mitochondrial mutations, A1555G, A7445G, and Cins7472, was performed on 27 of the relatives. All of the individuals tested had the normal sequence at the sites tested. This family with nonsyndromic sensorineural hearing loss has an inheritance pattern strongly suggestive of a mitochondrial mutation. However, molecular testing for the three known mitochondrial mutations associated with nonsyndromic hearing impairment was negative, implying that additional molecular defects can lead to the same phenotype. The search for this novel molecular defect is underway.

Methodology of a multistate study of congenital hearing loss: Preliminary data from Utah newborn screening

“…Mitochondrial A1555G and A7445G mutation detection is carried out as described by Friedman et al [1999] and Iwasaki et al [2000]. The assays of PCR amplification followed by restriction enzyme digestion were used for detecting the A1555G and A7445G mutations in mtDNA.…”

Non-syndromic Hearing Impairment in a Hungarian Family with the m.7510T>C Mutation of Mitochondrial tRNASer(UCN) and Review of Published Cases

“…Inherited as a matrilineal trait, sensorineural hearing loss (SNHL) can be attributed to mtDNA mutations. Isolated, non-syndromic hearing loss (OMIM #500008) has been associated classically with mitochondrial 12S rRNA (Prezant et al 1993) and tRNA Ser(UCN) genes (Friedman et al 1999), but recent genetic and functional studies suggest the role of further mitochondrial genes (Zheng et al 2012), such as the ND1 of complex I of the respiratory chain (m.3388C>A), the tRNA Ile (m.4295A>G), subunit COII of complex IV (m.8078G>A), the tRNA Ser(AGY) (m.12236G>A), the tRNA His (m.12201T>C) (Yan et al 2011), and Cytochrome B, subunit of complex III (m.15077G>A) (Gutiérrez Cortés et al 2012). Certain mutations can cause syndromic or isolated hearing impairment, as in the m.7445A>G mutation, leading to hearing loss with or without palmoplantar keratoderma (Reid et al 1994;Maász et al 2008), or in the m.7472insC mutation, responsible for hearing loss sometimes associated with a neurological disorder (Verhoeven et al 1999).…”

Mitochondrial rRNA and tRNA and hearing function

“…This mutation often exists in homoplasmy in most matrilineal relatives and in a high level of heteroplasmy in some matrilineal relatives. However, the levels of homoplasmy and heteroplasmy did not correlate with the severity and age of onset of hearing loss [49][50][51][52][53]. Despite sharing some common features, matrilineal relatives of intra-families or inter-families carrying the T7511C mutation exhibited variable severity, age of onset, and progression in hearing loss [49][50][51][52].…”

“…In the mitochondrial tRNA Ser(UCN) gene, five nonsyndromic deafness-associated mutations, A7445G [42][43][44], 7472insC [45][46][47], T7510C [48,84], T7511C [49][50][51][52][53], and G7444A [55][56][57], have been found in families from various ethnic backgrounds. These mutations often occur in homoplasmy or in high levels of heteroplasmy, indicating a high threshold for pathogenicity.…”

“…The T7511C mutation has been identified to be associated with nonsyndromic SNHL in several families from different ethnic groups, including African [49,50], French [52], and Japanese [51]. This mutation often exists in homoplasmy in most matrilineal relatives and in a high level of heteroplasmy in some matrilineal relatives.…”