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

• Published in: American journal of human genetics Vol. 85; no. 3; pp. 328 - 337
• Main Authors: Grillet, Nicolas, Schwander, Martin, Hildebrand, Michael S., Sczaniecka, Anna, Kolatkar, Anand, Velasco, Janice, Webster, Jennifer A., Kahrizi, Kimia, Najmabadi, Hossein, Kimberling, William J., Stephan, Dietrich, Bahlo, Melanie, Wiltshire, Tim, Tarantino, Lisa M., Kuhn, Peter, Smith, Richard J.H., Müller, Ulrich
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 01.09.2009; Cell Press; Elsevier
• Subjects: Amino Acid Sequence; Animals; Base Sequence; Biological and medical sciences; Carrier Proteins - chemistry; Carrier Proteins - genetics; Cells; Cilia - pathology; Cilia - ultrastructure; Codon, Terminator - genetics; Conserved Sequence; DNA Mutational Analysis; Ear, auditive nerve, cochleovestibular tract, facial nerve: diseases, semeiology; Evolution, Molecular; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genes; Genes, Recessive; Genetics of eukaryotes. Biological and molecular evolution; Hair Cells, Auditory, Outer - pathology; Hair Cells, Auditory, Outer - ultrastructure; Hearing loss; Hearing Loss - genetics; Hearing Loss - pathology; Heterogeneous-Nuclear Ribonucleoproteins - genetics; Humans; In Situ Hybridization; Medical genetics; Medical sciences; Membranes; Mice; Molecular and cellular biology; Molecular Sequence Data; Mutation; Mutation - genetics; Mutation, Missense - genetics; Nerve Degeneration - genetics; Nerve Degeneration - pathology; Non tumoral diseases; Otorhinolaryngology. Stomatology; Protein Structure, Secondary; Rodents; Spiral Ganglion - pathology; Spiral Ganglion - ultrastructure; Studies; Human; Hair; Cell function; Rodentia; Auditory disorder; Protein; Hearing loss; Hair (head); Progressive; Vertebrata; Mammalia; Mouse; Animal; ENT disease; Genetics; Mutation
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2009.07.017

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.