ABCC1 – Autosomal dominant nonsyndromic hearing loss

Extrusion pump ABCC1 was first implicated in autosomal dominant nonsyndromic hearing loss (Autosomal dominant nonsyndromic hearing loss) by stepwise genetic analysis in a Chinese pedigree (HN-SD01). A heterozygous missense variant, c.1769A>G (p.Asn590Ser), cosegregated with hearing impairment in multiple affected relatives of HN-SD01 ([PMID:31273342]). Screening of an additional 217 unrelated NSHL cases identified two more ABCC1 missense changes: c.692G>A (p.Gly231Asp) in a sporadic patient and c.887A>T (p.Glu296Val) in a familial proband ([PMID:31273342]).

Inheritance follows an autosomal dominant pattern, supported by segregation in one large family and independent occurrences in two others. Functional studies demonstrated cochlear expression of Abcc1 in mouse stria vascularis and auditory nerve. The p.Asn590Ser substitution disrupted membrane localization, reduced mRNA stability and impaired ABCC1 efflux capacity in cell assays ([PMID:31273342]).

Although only three probands across two families have been reported, the combination of segregation and mechanistic data supports a Limited gene–disease association. Further replication in additional cohorts and detailed segregation analyses are needed to establish definitive clinical validity. Key take-home: include ABCC1 in genetic testing panels for autosomal dominant NSHL when unexplained by established deafness genes.

References

• Genetics in medicine • 2019 • Extrusion pump ABCC1 was first linked with nonsyndromic hearing loss in humans by stepwise genetic analysis. PMID:31273342

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