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

Hela Azaiez, Amanda R. Decker, Kevin T. Booth, Allen C. Simpson, A. Eliot Shearer, Patrick L.M. Huygen, Fengxiao Bu, Michael S. Hildebrand, Paul T. Ranum, Seiji B. Shibata, Ann Turner, Yuzhou Zhang, William J Kimberling, Robert A. Cornell, Richard J.H. Smith

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1005137
JournalPLoS genetics
Volume11
Issue number3
DOIs
StatePublished - Mar 27 2015

Fingerprint

scaffolding proteins
hearing
Hearing Loss
Hearing
protein
mice
Deafness
Inner Ear
Proteins
deafness
Protein Multimerization
Stereocilia
Genes
Exome
High-Throughput Nucleotide Sequencing
gene
ears
Zebrafish
extended families
Tongue

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Azaiez, H., Decker, A. R., Booth, K. T., Simpson, A. C., Shearer, A. E., Huygen, P. L. M., ... Smith, R. J. H. (2015). HOMER2, a Stereociliary Scaffolding Protein, Is Essential for Normal Hearing in Humans and Mice. PLoS genetics, 11(3), [e1005137]. https://doi.org/10.1371/journal.pgen.1005137

HOMER2, a Stereociliary Scaffolding Protein, Is Essential for Normal Hearing in Humans and Mice. / Azaiez, Hela; Decker, Amanda R.; Booth, Kevin T.; Simpson, Allen C.; Shearer, A. Eliot; Huygen, Patrick L.M.; Bu, Fengxiao; Hildebrand, Michael S.; Ranum, Paul T.; Shibata, Seiji B.; Turner, Ann; Zhang, Yuzhou; Kimberling, William J; Cornell, Robert A.; Smith, Richard J.H.

In: PLoS genetics, Vol. 11, No. 3, e1005137, 27.03.2015.

Research output: Contribution to journalArticle

Azaiez, H, Decker, AR, Booth, KT, Simpson, AC, Shearer, AE, Huygen, PLM, Bu, F, Hildebrand, MS, Ranum, PT, Shibata, SB, Turner, A, Zhang, Y, Kimberling, WJ, Cornell, RA & Smith, RJH 2015, 'HOMER2, a Stereociliary Scaffolding Protein, Is Essential for Normal Hearing in Humans and Mice', PLoS genetics, vol. 11, no. 3, e1005137. https://doi.org/10.1371/journal.pgen.1005137
Azaiez H, Decker AR, Booth KT, Simpson AC, Shearer AE, Huygen PLM et al. HOMER2, a Stereociliary Scaffolding Protein, Is Essential for Normal Hearing in Humans and Mice. PLoS genetics. 2015 Mar 27;11(3). e1005137. https://doi.org/10.1371/journal.pgen.1005137
Azaiez, Hela ; Decker, Amanda R. ; Booth, Kevin T. ; Simpson, Allen C. ; Shearer, A. Eliot ; Huygen, Patrick L.M. ; Bu, Fengxiao ; Hildebrand, Michael S. ; Ranum, Paul T. ; Shibata, Seiji B. ; Turner, Ann ; Zhang, Yuzhou ; Kimberling, William J ; Cornell, Robert A. ; Smith, Richard J.H. / HOMER2, a Stereociliary Scaffolding Protein, Is Essential for Normal Hearing in Humans and Mice. In: PLoS genetics. 2015 ; Vol. 11, No. 3.
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