TY - JOUR
T1 - Mutations in OTOGL, encoding the inner ear protein otogelin-like, cause moderate sensorineural hearing loss
AU - Yariz, Kemal O.
AU - Duman, Duygu
AU - Seco, Celia Zazo
AU - Dallman, Julia
AU - Huang, Mingqian
AU - Peters, Theo A.
AU - Sirmaci, Asli
AU - Lu, Na
AU - Schraders, Margit
AU - Skromne, Isaac
AU - Oostrik, Jaap
AU - Diaz-Horta, Oscar
AU - Young, Juan I.
AU - Tokgoz-Yilmaz, Suna
AU - Konukseven, Ozlem
AU - Shahin, Hashem
AU - Hetterschijt, Lisette
AU - Kanaan, Moien
AU - Oonk, Anne M.M.
AU - Edwards, Yvonne J.K.
AU - Li, Huawei
AU - Atalay, Semra
AU - Blanton, Susan
AU - Desmidt, Alexandra A.
AU - Liu, Xue Zhong
AU - Pennings, Ronald J.E.
AU - Lu, Zhongmin
AU - Chen, Zheng Yi
AU - Kremer, Hannie
AU - Tekin, Mustafa
N1 - Funding Information:
We want to acknowledge the families for their participation in the study. This work was supported by National Institutes of Health grants R01DC009645 to M.T., R01 DC006908 to Z.-Y.C, R21 DC009879 to Z. L., RO1DC05575 to X.-Z.L., the Fredrick and Ines Yeatts Inner Ear Hair Cell Regeneration Fellowship to M.H. and N.L., the Heinsius Houbolt Foundation to H.K., the Oticon Foundation (09-3742) to H.K., ZonMW to H.K. (40-00812-98-09047) and R.J.E.P. (90700388), and the RNID (GR36) to H.K. N.L. was supported by a grant from the China Scholarship Council, P.R. China. X.Z.L. was supported by Hurong Scholar Award in Hunan, China. Z.L. and J.D. were supported by the University of Miami Provost Research Award and College of Arts. Z.L. was supported by Sciences Gabelli Fellowship. I.S. was supported by National Science Foundation grant IOS-0920449 and by the University of Miami Provost Research Award. We are grateful to Atlas Antibodies for providing the OTOGL immunogenic peptide.
PY - 2012/11/2
Y1 - 2012/11/2
N2 - 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.Val477Glufs25) 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.
AB - 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.Val477Glufs25) 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.
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U2 - 10.1016/j.ajhg.2012.09.011
DO - 10.1016/j.ajhg.2012.09.011
M3 - Article
C2 - 23122586
AN - SCOPUS:84868347148
VL - 91
SP - 872
EP - 882
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 5
ER -