A forward genetics screen in mice identifies recessive deafness traits and reveals that pejvakin is essential for outer hair cell function.
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.
Schwander
Martin
M
Department of Cell Biology, Institute for Childhood and Neglected Disease, The Scripps Research Institute, La Jolla, California 92037, USA.
Sczaniecka
Anna
A
Grillet
Nicolas
N
Bailey
Janice S
JS
Avenarius
Matthew
M
Najmabadi
Hossein
H
Steffy
Brian M
BM
Federe
Glenn C
GC
Lagler
Erica A
EA
Banan
Raheleh
R
Hice
Rudy
R
Grabowski-Boase
Laura
L
Keithley
Elisabeth M
EM
Ryan
Allen F
AF
Housley
Gary D
GD
Wiltshire
Tim
T
Smith
Richard J H
RJ
Tarantino
Lisa M
LM
Müller
Ulrich
U
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
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