title: Mutations in OTOGL, encoding the inner ear protein otogelin-like, cause moderate sensorineural hearing loss.
abstract: Hereditary hearing loss is characterized by a high degree of genetic heterogeneity. Here we present OTOGL mutations, a homozygous one base pair deletion (c.1430 delT) causing a frameshift (p.Val477Glufs(∗)25) in a large consanguineous family and two compound heterozygous mutations, c.547C>T (p.Arg183(∗)) and c.5238+5G>A, in a nonconsanguineous family with moderate nonsyndromic sensorineural hearing loss. OTOGL maps to the DFNB84 locus at 12q21.31 and encodes otogelin-like, which has structural similarities to the epithelial-secreted mucin protein family. We demonstrate that Otogl is expressed in the inner ear of vertebrates with a transcription level that is high in embryonic, lower in neonatal, and much lower in adult stages. Otogelin-like is localized to the acellular membranes of the cochlea and the vestibular system and to a variety of inner ear cells located underneath these membranes. Knocking down of otogl with morpholinos in zebrafish leads to sensorineural hearing loss and anatomical changes in the inner ear, supporting that otogelin-like is essential for normal inner ear function. We propose that OTOGL mutations affect the production and/or function of acellular structures of the inner ear, which ultimately leads to sensorineural hearing loss.
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Kemal O
authors.initials: KO
authors.lastname: Yariz
authors.forename: Duygu
authors.initials: D
authors.lastname: Duman
authors.forename: Celia
authors.initials: C
authors.lastname: Zazo Seco
authors.forename: Julia
authors.initials: J
authors.lastname: Dallman
authors.forename: Mingqian
authors.initials: M
authors.lastname: Huang
authors.forename: Theo A
authors.initials: TA
authors.lastname: Peters
authors.forename: Asli
authors.initials: A
authors.lastname: Sirmaci
authors.forename: Na
authors.initials: N
authors.lastname: Lu
authors.forename: Margit
authors.initials: M
authors.lastname: Schraders
authors.forename: Isaac
authors.initials: I
authors.lastname: Skromne
authors.forename: Jaap
authors.initials: J
authors.lastname: Oostrik
authors.forename: Oscar
authors.initials: O
authors.lastname: Diaz-Horta
authors.forename: Juan I
authors.initials: JI
authors.lastname: Young
authors.forename: Suna
authors.initials: S
authors.lastname: Tokgoz-Yilmaz
authors.forename: Ozlem
authors.initials: O
authors.lastname: Konukseven
authors.forename: Hashem
authors.initials: H
authors.lastname: Shahin
authors.forename: Lisette
authors.initials: L
authors.lastname: Hetterschijt
authors.forename: Moien
authors.initials: M
authors.lastname: Kanaan
authors.forename: Anne M M
authors.initials: AM
authors.lastname: Oonk
authors.forename: Yvonne J K
authors.initials: YJ
authors.lastname: Edwards
authors.forename: Huawei
authors.initials: H
authors.lastname: Li
authors.forename: Semra
authors.initials: S
authors.lastname: Atalay
authors.forename: Susan
authors.initials: S
authors.lastname: Blanton
authors.forename: Alexandra A
authors.initials: AA
authors.lastname: Desmidt
authors.forename: Xue-Zhong
authors.initials: XZ
authors.lastname: Liu
authors.forename: Ronald J E
authors.initials: RJ
authors.lastname: Pennings
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Lu
authors.forename: Zheng-Yi
authors.initials: ZY
authors.lastname: Chen
authors.forename: Hannie
authors.initials: H
authors.lastname: Kremer
authors.forename: Mustafa
authors.initials: M
authors.lastname: Tekin
mesh_terms: D000293:Adolescent; D000818:Animals; D002675:Child, Preschool; D002869:Chromosome Aberrations; D003051:Cochlea / Q000378:metabolism / Q000473:pathology; D059472:Exome; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D054643:INDEL Mutation; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D051381:Rats; D015027:Zebrafish
chemical_list: D008565:Membrane Proteins; C577332:OTOGL protein, human