ClinVar Genomic variation as it relates to human health

Visual impairment (present) , Morphological central nervous system abnormality (present) , Progressive visual loss (present) , Sensorineural hearing loss disorder (present) , Postlingual sensorineural hearing impairment (present) , Childhood onset sensorineural hearing impairment (present) , Visual loss (present) , Optic atrophy (present) (less)

In a Japanese patient with optic atrophy and moderate sensorineural deafness (125250), Shimizu et al. (2003) identified a heterozygous G-to-A transition in the second nucleotide at codon 445 in the OPA1 gene, resulting in an arg445-to-his (R445H) substitution in the GTPase domain. Payne et al. (2004) found this mutation in a large Utah family and an unrelated Belgian family, previously described by Treft et al. (1984) and Meire et al. (1985), respectively. Both families had optic atrophy, deafness, and ophthalmoplegia. The authors hypothesized that, although OPA1 is a nuclear gene, the localization of its gene product to mitochondria suggests that mitochondrial dysfunction might be the final common pathway for many forms of syndromic and nonsyndromic optic atrophy, hearing loss, and external ophthalmoplegia. In a third family with optic atrophy and hearing loss, unrelated to the Utah or Belgian families, Li et al. (2005) identified the R445H mutation. Li et al. (2005) noted that affected members of this family did not have extraocular motility abnormalities or ptosis, thus illustrating the intra- and interfamilial phenotype variability associated with this mutation. Amati-Bonneau et al. (2005) identified the R445H mutation in 5 unrelated patients from 4 families with optic atrophy and deafness, thus confirming that this mutation is specifically associated with hearing loss. One of the patients had been previously reported by Amati-Bonneau et al. (2003). In the Spanish mother and daughter previously reported by Amati-Bonneau et al. (2005), Amati-Bonneau et al. (2008) noted that the mother had additional features including myopathy, neuropathy, and progressive external ophthalmoplegia. Stewart et al. (2008) identified the R445H mutation in 2 probands with optic atrophy and myopathy associated with mitochondrial DNA deletions. One proband also had deafness. The other proband did not have hearing loss, but 3 affected family members had hearing loss. In a 27-year-old Italian woman and her 57-year-old mother with DOA+, Napolitano et al. (2020) identified heterozygosity for the mutation in the OPA1 gene (R445H; 605290.0011). The mutation was identified by Sanger sequencing of the OPA1 gene. The daughter had reduced visual acuity, deafness, and myopathy, and her mother had amaurosis, deafness, extraocular muscle palsy, and severe ataxia. Expression of HTRA2 (606441) was increased in the muscle tissue of both patients, although more so in the daughter. Napolitano et al. (2020) hypothesized that OPA1 mutations may induce HTRA2 overexpression, and variable expression of HTRA2 may contribute to disease variability in optic atrophy and deafness in patients with the same OPA1 mutation. (less)