Mutations in LOXHD1, an Evolutionarily Conserved Stereociliary Protein, Disrupt Hair Cell Function in Mice and Cause Progressive Hearing Loss in Humans

Nicolas Grillet; Martin Schwander; Michael S. Hildebrand; Anna Sczaniecka; Anand Kolatkar; Janice Velasco; Jennifer A. Webster; Kimia Kahrizi; Hossein Najmabadi; William J. Kimberling; Dietrich Stephan; Melanie Bahlo; Tim Wiltshire; Lisa M. Tarantino; Peter Kuhn; Richard J.H. Smith; Ulrich Müller

doi:10.1016/j.ajhg.2009.07.017

Mutations in LOXHD1, an Evolutionarily Conserved Stereociliary Protein, Disrupt Hair Cell Function in Mice and Cause Progressive Hearing Loss in Humans

Nicolas Grillet
, Martin Schwander
, Michael S. Hildebrand
, Anna Sczaniecka
, Anand Kolatkar
, Janice Velasco
, Jennifer A. Webster
, Kimia Kahrizi
, Hossein Najmabadi
, William J. Kimberling
, Dietrich Stephan
, Melanie Bahlo
, Tim Wiltshire
, Lisa M. Tarantino
, Peter Kuhn
, Richard J.H. Smith
, Ulrich Müller

Research output: Contribution to journal › Article › peer-review

137 Citations (SciVal)

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/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.

Original language	English
Pages (from-to)	328-337
Number of pages	10
Journal	American Journal of Human Genetics
Volume	85
Issue number	3
DOIs	https://doi.org/10.1016/j.ajhg.2009.07.017
State	Published - Sep 11 2009

Funding

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.

Funders	Funder number
Australian National Health and Medical Research Council
Bruce Ford and Anne Smith Bundy Foundation
National Institute on Deafness and Other Communication Disorders	R01DC007704, DC002842, DC005965
Skaggs Institute for Chemical Biology, Scripps Research Institute

ASJC Scopus subject areas

Genetics
Genetics(clinical)

Access to Document

10.1016/j.ajhg.2009.07.017

Cite this

Grillet, N., Schwander, M., Hildebrand, M. S., Sczaniecka, A., Kolatkar, A., Velasco, J., Webster, J. A., Kahrizi, K., Najmabadi, H., Kimberling, W. J., Stephan, D., Bahlo, M., Wiltshire, T., Tarantino, L. M., Kuhn, P., Smith, R. J. H., & Müller, U. (2009). Mutations in LOXHD1, an Evolutionarily Conserved Stereociliary Protein, Disrupt Hair Cell Function in Mice and Cause Progressive Hearing Loss in Humans. American Journal of Human Genetics, 85(3), 328-337. https://doi.org/10.1016/j.ajhg.2009.07.017

@article{d6c7c0fdb15b46938f9db3198a52aa65,

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/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.",

author = "Nicolas Grillet and Martin Schwander and Hildebrand, \{Michael S.\} and Anna Sczaniecka and Anand Kolatkar and Janice Velasco and Webster, \{Jennifer A.\} and Kimia Kahrizi and Hossein Najmabadi and Kimberling, \{William J.\} and Dietrich Stephan and Melanie Bahlo and Tim Wiltshire and Tarantino, \{Lisa M.\} and Peter Kuhn and Smith, \{Richard J.H.\} and Ulrich M{\"u}ller",

year = "2009",

month = sep,

day = "11",

doi = "10.1016/j.ajhg.2009.07.017",

language = "English",

volume = "85",

pages = "328--337",

number = "3",

}

Grillet, N, Schwander, M, Hildebrand, MS, Sczaniecka, A, Kolatkar, A, Velasco, J, Webster, JA, Kahrizi, K, Najmabadi, H, Kimberling, WJ, Stephan, D, Bahlo, M, Wiltshire, T, Tarantino, LM, Kuhn, P, Smith, RJH & Müller, U 2009, 'Mutations in LOXHD1, an Evolutionarily Conserved Stereociliary Protein, Disrupt Hair Cell Function in Mice and Cause Progressive Hearing Loss in Humans', American Journal of Human Genetics, vol. 85, no. 3, pp. 328-337. https://doi.org/10.1016/j.ajhg.2009.07.017

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

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.

UR - https://www.scopus.com/pages/publications/69449086147

UR - https://www.scopus.com/pages/publications/69449086147#tab=citedBy

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 -

Mutations in LOXHD1, an Evolutionarily Conserved Stereociliary Protein, Disrupt Hair Cell Function in Mice and Cause Progressive Hearing Loss in Humans

Abstract

Funding

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this