Deafness, Sensorineural, Autosomal-Mitochondrial Type

Clinical Features

Jaber et al. (1992) presented the findings in a large Israeli Arab kindred with hereditary deafness. Fifty-five deaf subjects (29 male, 26 female), who were otherwise healthy, were traced back 5 generations to a common female ancestor. The deafness was progressive and usually presented in infancy or childhood. Audiometry was consistent with severe to profound sensorineural hearing loss.

Inheritance

Formal segregation analysis suggested that the inheritance of deafness in a large Israeli Arab kindred closely fitted the expectation of a 2-locus model consisting of the simultaneous mutation of an autosomal recessive gene and a mitochondrial gene (Jaber et al., 1992). Mitochondrial DNA analysis showed no evidence for deletions or duplications or for heteroplasmy.

In the family with deafness reported by Jaber et al. (1992), Prezant et al. (1992) reported biochemical studies directed at mitochondrial function.

The finding of a mutation in the MTRNR1 gene (561000.0001) by Prezant et al. (1993) in the family reported by Jaber et al. (1992) confirmed mitochondrial inheritance. Family members with the mutation had phenotypes ranging from profound hearing loss to completely normal hearing, and Bu et al. (1992) and Guan et al. (1996) presented genetic and biochemical evidence for nuclear gene involvement.

By linkage analysis, Bykhovskaya et al. (1998) could demonstrate no chromosomal region as a major contributor to the variation in the phenotypic expression of the mitochondrial mutation. They suggested that in this simplified paradigm of a homoplasmic mitochondrial mutation in a single kindred who all live in a similar environment of a small village, the penetrance of the mitochondrial mutation depends on the interaction of multiple nuclear genes.

Nadeau (2001) reviewed modifier genes in mice and humans and pointed to the findings of Bykhovskaya et al. (2000) as an example of a modifier effect on penetrance.

Molecular Genetics

Prezant et al. (1993) demonstrated a homoplasmic 1555A-G (561000.0001) mutation in the mitochondrial 12S ribosomal RNA gene (MTRNR1) in the family reported by Jaber et al. (1992).

Mapping

Bykhovskaya et al. (2000) studied 10 multiplex Spanish and Italian families with 35 members with the 1555A-G mutation (561000.0001) and sensorineural deafness. Nonparametric analysis supported the role of the chromosomal region around marker D8S277, with a combined maximized allele-sharing lod score of 3.1 in Arab-Israeli/Spanish/Italian families.

Bykhovskaya et al. (2001) obtained 47 DNAs from members of 5 multiplex families from Spain, 1 from Italy, and 1 nuclear family from Finland with matrilineal nonsyndromic hearing loss, showing a combined lod score of 4.0 in the region of markers D8S277, D8S561, and D8S1819. This finding represented the first identification of a modifier locus for a human mitochondrial DNA disease and supported the concept of mitochondrial DNA diseases having complex inheritance. This modifier gene would be a susceptibility gene and would probably not be sufficient to cause disease in the absence of homoplasmy for the 1555A-G mutation.

Finnala and Majamaa (2003) performed fine mapping of the region around marker D8S277 in a large Finnish family with nonsyndromic sensorineural hearing loss, 3 members of which had been part of the study by Bykhovskaya et al. (2001). Haplotype comparison of 9 affected and 7 unaffected persons excluded the region around 8p23 as the site of a susceptibility locus for hearing impairment in this family.