title: A forward genetics screen in mice identifies recessive deafness traits and reveals that pejvakin is essential for outer hair cell function.
abstract: Deafness is the most common form of sensory impairment in the human population and is frequently caused by recessive mutations. To obtain animal models for recessive forms of deafness and to identify genes that control the development and function of the auditory sense organs, we performed a forward genetics screen in mice. We identified 13 mouse lines with defects in auditory function and six lines with auditory and vestibular defects. We mapped several of the affected genetic loci and identified point mutations in four genes. Interestingly, all identified genes are expressed in mechanosensory hair cells and required for their function. One mutation maps to the pejvakin gene, which encodes a new member of the gasdermin protein family. Previous studies have described two missense mutations in the human pejvakin gene that cause nonsyndromic recessive deafness (DFNB59) by affecting the function of auditory neurons. In contrast, the pejvakin allele described here introduces a premature stop codon, causes outer hair cell defects, and leads to progressive hearing loss. We also identified a novel allele of the human pejvakin gene in an Iranian pedigree that is afflicted with progressive hearing loss. Our findings suggest that the mechanisms of pathogenesis associated with pejvakin mutations are more diverse than previously appreciated. More generally, our findings demonstrate that recessive screens in mice are powerful tools for identifying genes that control the development and function of mechanosensory hair cells and cause deafness in humans, as well as generating animal models for disease.
authors.affiliation: Department of Cell Biology, Institute for Childhood and Neglected Disease, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Schwander
authors.forename: Anna
authors.initials: A
authors.lastname: Sczaniecka
authors.forename: Nicolas
authors.initials: N
authors.lastname: Grillet
authors.forename: Janice S
authors.initials: JS
authors.lastname: Bailey
authors.forename: Matthew
authors.initials: M
authors.lastname: Avenarius
authors.forename: Hossein
authors.initials: H
authors.lastname: Najmabadi
authors.forename: Brian M
authors.initials: BM
authors.lastname: Steffy
authors.forename: Glenn C
authors.initials: GC
authors.lastname: Federe
authors.forename: Erica A
authors.initials: EA
authors.lastname: Lagler
authors.forename: Raheleh
authors.initials: R
authors.lastname: Banan
authors.forename: Rudy
authors.initials: R
authors.lastname: Hice
authors.forename: Laura
authors.initials: L
authors.lastname: Grabowski-Boase
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Keithley
authors.forename: Allen F
authors.initials: AF
authors.lastname: Ryan
authors.forename: Gary D
authors.initials: GD
authors.lastname: Housley
authors.forename: Tim
authors.initials: T
authors.lastname: Wiltshire
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Tarantino
authors.forename: Ulrich
authors.initials: U
authors.lastname: Müller
mesh_terms: D000818:Animals; D001483:Base Sequence; D002874:Chromosome Mapping; D003638:Deafness / Q000139:chemically induced / Q000235:genetics*; D004195:Disease Models, Animal; D005038:Ethylnitrosourea / Q000031:analogs & derivatives; D005260:Female; D005808:Genes, Recessive; D005820:Genetic Testing; D018072:Hair Cells, Auditory, Outer / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009153:Mutagens; D009363:Neoplasm Proteins / Q000378:metabolism*; D010375:Pedigree; D017354:Point Mutation; D011595:Psychomotor Agitation / Q000235:genetics; D016415:Sequence Alignment; D000094524:Gasdermins
chemical_list: D005038:Ethylnitrosourea; D008565:Membrane Proteins; D009153:Mutagens; D009363:Neoplasm Proteins; C413482:Gsdma protein, mouse; D000094524:Gasdermins; C516233:otoferlin protein, mouse; C061089:1-nitroso-1-ethyl-3-methylurea