TY - JOUR
T1 - Mutations in LOXHD1, an Evolutionarily Conserved Stereociliary Protein, Disrupt Hair Cell Function in Mice and Cause Progressive Hearing Loss in Humans
AU - Grillet, Nicolas
AU - Schwander, Martin
AU - Hildebrand, Michael S.
AU - Sczaniecka, Anna
AU - Kolatkar, Anand
AU - Velasco, Janice
AU - Webster, Jennifer A.
AU - Kahrizi, Kimia
AU - Najmabadi, Hossein
AU - Kimberling, William J.
AU - Stephan, Dietrich
AU - Bahlo, Melanie
AU - Wiltshire, Tim
AU - Tarantino, Lisa M.
AU - Kuhn, Peter
AU - Smith, Richard J.H.
AU - Müller, Ulrich
N1 - Funding Information:
The authors sincerely thank the family for their participation in this study. They would also like to thank D. McCarthy for help with data assembly and K. Crozat and D. Logan for sharing expertise in fine mapping and bioinformatics. This research was funded by NIDCD grants DC007704, DC005965 (U.M.), and DC002842 (R.J.H.S.), the Skaggs Institute for Chemical Biology (U.M.), a fellowship from the Bruce Ford and Anne Smith Bundy Foundation (N.G.), an Australian National Health and Medical Research Council (NHMRC) Career Development Award (M.B.), and an NHMRC Overseas Biomedical Fellowship (M.S.H.). R.J.H.S. is the Sterba Hearing Research Professor, University of Iowa College of Medicine.
PY - 2009/9/11
Y1 - 2009/9/11
N2 - 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/α-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.
AB - 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/α-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.
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U2 - 10.1016/j.ajhg.2009.07.017
DO - 10.1016/j.ajhg.2009.07.017
M3 - Article
C2 - 19732867
AN - SCOPUS:69449086147
SN - 0002-9297
VL - 85
SP - 328
EP - 337
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 3
ER -