title: Auditory hair cell defects as potential cause for sensorineural deafness in Wolf-Hirschhorn syndrome.
abstract: WHSC1 is a histone methyltransferase (HMT) that catalyses the addition of methyl groups to lysine 36 on histone 3. In humans, WHSC1 haploinsufficiency is associated with all known cases of Wolf-Hirschhorn syndrome (WHS). The cardinal feature of WHS is a craniofacial dysmorphism, which is accompanied by sensorineural hearing loss in 15% of individuals with WHS. Here, we show that WHSC1-deficient mice display craniofacial defects that overlap with WHS, including cochlea anomalies. Although auditory hair cells are specified normally, their stereocilia hair bundles required for sound perception fail to develop the appropriate morphology. Furthermore, the orientation and cellular organisation of cochlear hair cells and their innervation are defective. These findings identify, for the first time, the likely cause of sensorineural hearing loss in individuals with WHS.
authors.affiliation: Department of Craniofacial Development and Stem Cell Biology, King's College London, London, SE1 9RT, UK.
authors.forename: Mohi
authors.initials: M
authors.lastname: Ahmed
authors.affiliation: Laboratory of Chromatin Metabolism and Epigenetics, Graduate School of Science, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan PRESTO, Japan Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan.
authors.forename: Kiyoe
authors.initials: K
authors.lastname: Ura
authors.affiliation: Department of Craniofacial Development and Stem Cell Biology, King's College London, London, SE1 9RT, UK andrea.streit@kcl.ac.uk.
authors.forename: Andrea
authors.initials: A
authors.lastname: Streit
mesh_terms: D000818:Animals; D003051:Cochlea / Q000002:abnormalities / Q000196:embryology / Q000473:pathology; D004195:Disease Models, Animal; D017353:Gene Deletion; D006198:Hair Cells, Auditory / Q000473:pathology*; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006579:Heterozygote; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D006801:Humans; D015994:Incidence; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010641:Phenotype; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics; D015398:Signal Transduction; D054877:Wolf-Hirschhorn Syndrome / Q000235:genetics*
chemical_list: D006657:Histones; D011495:Histone-Lysine N-Methyltransferase; C543213:WHSC1 protein, mouse; C496366:Fgfr3 protein, mouse; D051498:Receptor, Fibroblast Growth Factor, Type 3
keywords: Deafness; Ear; Hair cells; Histone modification; Methyltransferase; Mouse; Stereocilia