title: Mutations in LOXHD1, an evolutionarily conserved stereociliary protein, disrupt hair cell function in mice and cause progressive hearing loss in humans.
abstract: Hearing loss is the most common form of sensory impairment in humans and is frequently progressive in nature. Here we link a previously uncharacterized gene to hearing impairment in mice and humans. We show that hearing loss in the ethylnitrosourea (ENU)-induced samba mouse line is caused by a mutation in Loxhd1. LOXHD1 consists entirely of PLAT (polycystin/lipoxygenase/alpha-toxin) domains and is expressed along the membrane of mature hair cell stereocilia. Stereociliary development is unaffected in samba mice, but hair cell function is perturbed and hair cells eventually degenerate. Based on the studies in mice, we screened DNA from human families segregating deafness and identified a mutation in LOXHD1, which causes DFNB77, a progressive form of autosomal-recessive nonsyndromic hearing loss (ARNSHL). LOXHD1, MYO3a, and PJVK are the only human genes to date linked to progressive ARNSHL. These three genes are required for hair cell function, suggesting that age-dependent hair cell failure is a common mechanism for progressive ARNSHL.
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Grillet
authors.forename: Martin
authors.initials: M
authors.lastname: Schwander
authors.forename: Michael S
authors.initials: MS
authors.lastname: Hildebrand
authors.forename: Anna
authors.initials: A
authors.lastname: Sczaniecka
authors.forename: Anand
authors.initials: A
authors.lastname: Kolatkar
authors.forename: Janice
authors.initials: J
authors.lastname: Velasco
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Webster
authors.forename: Kimia
authors.initials: K
authors.lastname: Kahrizi
authors.forename: Hossein
authors.initials: H
authors.lastname: Najmabadi
authors.forename: William J
authors.initials: WJ
authors.lastname: Kimberling
authors.forename: Dietrich
authors.initials: D
authors.lastname: Stephan
authors.forename: Melanie
authors.initials: M
authors.lastname: Bahlo
authors.forename: Tim
authors.initials: T
authors.lastname: Wiltshire
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Tarantino
authors.forename: Peter
authors.initials: P
authors.lastname: Kuhn
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
authors.forename: Ulrich
authors.initials: U
authors.lastname: Müller
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics*; D002923:Cilia / Q000473:pathology / Q000648:ultrastructure; D018388:Codon, Terminator / Q000235:genetics; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D019143:Evolution, Molecular; D005808:Genes, Recessive; D018072:Hair Cells, Auditory, Outer / Q000473:pathology* / Q000648:ultrastructure; D034381:Hearing Loss / Q000235:genetics* / Q000473:pathology; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology; D017433:Protein Structure, Secondary; D013136:Spiral Ganglion / Q000473:pathology / Q000648:ultrastructure
chemical_list: D002352:Carrier Proteins; D018388:Codon, Terminator; D034441:Heterogeneous-Nuclear Ribonucleoproteins; C543906:LOXHD1 protein, human; C543905:LOXHD1 protein, mouse