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DEAFNESS, AUTOSOMAL DOMINANT 77; DFNA77

DEAFNESS, AUTOSOMAL DOMINANT 77; DFNA77

Li et al. (2019) reported a 5-generation Han Chinese family in which at least 13 individuals had adult-onset progressive hearing loss. Most affected individuals ...

Li et al. (2019) reported a 5-generation Han Chinese family in which at least 13 individuals had adult-onset progressive hearing loss. Most affected individuals developed hearing loss affecting high frequencies between the second and third decades of life. The hearing loss subsequently affected all frequencies by the fourth or fifth decades. There was no excessive noise exposure, special medication history, or complaints of other systemic abnormalities. Detailed auditory clinical examinations excluded auditory neuropathy disorders and inner ear malformations. Vestibular dysfunction and tinnitus were not noted.

▼ Inheritance
The transmission pattern of DFNA77 in the family reported by Li et al. (2019) was consistent with autosomal dominant inheritance with age-dependent penetrance.

▼ Molecular Genetics
In 10 affected members of a multigenerational Han Chinese family (family HN-SD01) with DFNA77, Li et al. (2019) identified a heterozygous missense mutation in the ABCC1 gene (N590S; 158343.0001). The mutation, which was found by a combination of linkage analysis and exome sequencing, segregated with the disorder in the family. Three unaffected or possibly affected members of the youngest generation also carried the mutation, suggesting age-dependent penetrance of the phenotype. In vitro functional expression studies of patient-derived lymphoblastoid cells showed transiently decreased efflux capacity of an ABCC1 substrate compared to controls; however, by 6 hours, the efflux was the same between patient cells and controls. Screening of ABCC1 in an additional 217 patients with hearing loss identified heterozygous candidate pathogenic variants in 2 patients (G231D and E296V). Both variants were absent in the ExAC and gnomAD databases. However, familial segregation for these patients was not possible, and functional studies of these variants were not performed. Li et al. (2019) postulated that ABCC1 may exhibit a protective role in maintaining the homeostasis of the inner ear; decreased activity of this efflux pump may lead to impairment of inner ear function, resulting in late-onset hearing loss.

Tags: 16p13.11