title: 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.
authors: Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology University of Iowa, Iowa City, Iowa, United States of America.
authors: Hela
authors: H
authors: Azaiez
authors: Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors: Amanda R
authors: AR
authors: Decker
authors: Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology University of Iowa, Iowa City, Iowa, United States of America.
authors: Kevin T
authors: KT
authors: Booth
authors: Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology University of Iowa, Iowa City, Iowa, United States of America.
authors: Allen C
authors: AC
authors: Simpson
authors: Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology University of Iowa, Iowa City, Iowa, United States of America.
authors: A Eliot
authors: AE
authors: Shearer
authors: Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.
authors: Patrick L M
authors: PL
authors: Huygen
authors: Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology University of Iowa, Iowa City, Iowa, United States of America.
authors: Fengxiao
authors: F
authors: Bu
authors: Austin Health, Department of Medicine, University of Melbourne, Melbourne, Australia.
authors: Michael S
authors: MS
authors: Hildebrand
authors: Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology University of Iowa, Iowa City, Iowa, United States of America.
authors: Paul T
authors: PT
authors: Ranum
authors: Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology University of Iowa, Iowa City, Iowa, United States of America.
authors: Seiji B
authors: SB
authors: Shibata
authors: Self-employed physician, Menlo Park, California, United States of America.
authors: Ann
authors: A
authors: Turner
authors: Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology University of Iowa, Iowa City, Iowa, United States of America.
authors: Yuzhou
authors: Y
authors: Zhang
authors: Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology University of Iowa, Iowa City, Iowa, United States of America.
authors: William J
authors: WJ
authors: Kimberling
authors: Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors: Robert A
authors: RA
authors: Cornell
authors: Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology University of Iowa, Iowa City, Iowa, United States of America; Interdepartmental PhD Program in Genetics, University of Iowa, Iowa City, Iowa, United States of America.
authors: Richard J H
authors: RJ
authors: Smith
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D003051:Cochlea / Q000378:metabolism / Q000473:pathology; D007758:Ear, Inner / Q000378:metabolism* / Q000473:pathology; D059472:Exome / Q000235:genetics*; D005786:Gene Expression Regulation; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing; D000072233:Homer Scaffolding Proteins; D006801:Humans; D051379:Mice; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D059547:Stereocilia / Q000235:genetics / Q000473:pathology; D015027:Zebrafish; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D000072233:Homer Scaffolding Proteins; C000606625:Homer2 protein, mouse; D012333:RNA, Messenger; D020764:cdc42 GTP-Binding Protein