HOMER2, a Stereociliary Scaffolding Protein, Is Essential for Normal Hearing in Humans and Mice

Abstract

Hereditary hearing loss is a clinically and genetically heterogeneous disorder. More than 80 genes have been implicated to date, and with the advent of targeted genomic enrichment and massively parallel sequencing (TGE+MPS) the rate of novel deafness-gene identification has accelerated. Here we report a family segregating post-lingual progressive autosomal dominant non-syndromic hearing loss (ADNSHL). After first excluding plausible variants in known deafness-causing genes using TGE+MPS, we completed whole exome sequencing in three hearing-impaired family members. Only a single variant, p.Arg185Pro in HOMER2, segregated with the hearing-loss phenotype in the extended family. This amino acid change alters a highly conserved residue in the coiled-coil domain of HOMER2 that is essential for protein multimerization and the HOMER2-CDC42 interaction. As a scaffolding protein, HOMER2 is involved in intracellular calcium homeostasis and cytoskeletal organization. Consistent with this function, we found robust expression in stereocilia of hair cells in the murine inner ear and observed that over-expression of mutant p.Pro185 HOMER2 mRNA causes anatomical changes of the inner ear and neuromasts in zebrafish embryos. Furthermore, mouse mutants homozygous for the targeted deletion of Homer2 present with early-onset rapidly progressive hearing loss. These data provide compelling evidence that HOMER2 is required for normal hearing and that its sequence alteration in humans leads to ADNSHL through a dominant-negative mode of action.

Whole exome sequencing identified a second pathogenic variant in HOMER2 for autosomal dominant non‐syndromic deafness

“…Pure tone audiograms showed that six affected family‐202 members (aged 25‐65) possessed binaural mean thresholds >80 dB HL for stimuli of 1 to 8 kHz (Figure B). Corresponding to the thresholds of family‐202 members, in the European family, the youngest patient with hearing thresholds increased to 60 dB HL at 1, 2, 4 and 8 kHz was aged 28 to 29 . According to ARTA of the two families, the average ages with hearing thresholds ≥60 dB HL at mid and high frequencies were 10 years in family‐202 (Figure B), and over 40 years in the European family .…”

“…The clinical manifestations of the two families were clearly different. In contrast to the European family, the earliest clinical evidence was obtained at an earlier age and hearing impairment was more severe in family‐202, namely, 7 years old with severe hearing loss (PTA = 63.75 dB HL) (Figure B) vs 8.6 years old with mild hearing loss (26 dB HL < PTA < 40 dB HL) in the European family . Pure tone audiograms showed that six affected family‐202 members (aged 25‐65) possessed binaural mean thresholds >80 dB HL for stimuli of 1 to 8 kHz (Figure B).…”

“…In this study, we identified a heterozygous variant c.840_841insC in HOMER2 gene in a Chinese pedigree with SNHL. The c.840_841insC variant is novel and is considered to be the pathogenic variant because: (1) the variant segregated with the ADNSHL phenotype in the extended family, but was absent in 77 patients with sporadic hearing loss, or in 117 control individuals with normal hearing; (2) the variant lying in the CC domain leads to a frameshift and a premature stop codon producing a truncated CC domain in the HOMER2 protein (aa288); this is a significant domain for multimerization or interaction with partner proteins; and (3) it has been reported that HOMER2 gene is essential for normal hearing in humans and mice . Family‐202 is the second family reported to have the HOMER2 deafness‐causing variant, providing validating evidence that HOMER2 is a new gene for late‐onset progressive HHL.…”

“…HOMER2 is required for normal hearing . The complete absence of Homer2 in mice leads to early onset progressive hearing loss, while Homer2 +/− mice lack this disease phenotype, suggesting that haploinsufficiency does not cause hearing loss .…”

“…Audiological tests were performed in a soundproof room according to clinical standards. Audiograms of seven affected family members were used to calculate age‐related typical audiograms (ARTA), as described by Huygen et al and an arbitrary value of 110 dB HL was used to indicate out‐of‐scale measurements …”