Yufei Feng
Sofia A. Rahman
Shuilong Wu
Guoan Li
Franz Rüschendorf
Lei Zhao
Hongwei Cui
Junqing Liang
Liang Fang
Hao Hu
Sebastian Froehler
Yong Yu
Giannino Patone
Oliver Hummel
Qinghua Chen
Klemens Raile
Friedrich C. Luft
Sylvia B?hring
Khalid Hussain
Wei Chen
Jingjing Zhang
Maolian Gong
aClinical Medicine Research Center, Affiliated Hospital of Inner Mongolia Medical University, Huhhot, 010050, China
bAffiliated Hospital of Guangdong Medical University & Key Laboratory of Zebrafish Model for Development and Disease of Guangdong Medical University, Zhanjiang, 524001, China
cMarine Medical Research Institute of Guangdong Zhanjiang, Zhanjiang, 524023, China
dGenomic Medicine Programme, UCL Institute of Child Health and Great Ormond Street Hospital for Children, 30 Guilford Street, London, WC1N 1EH, UK
eMax-Delbrueck-Center for Molecular Medicine (MDC), Robert-Roessle-Str.10, Berlin, 13125, Germany
fDepartment of Radiology, Affiliated Hospital of Inner Mongolia Medical University, Huhhot, 010050, China
gAffiliated People Hospital of Inner Mongolia Medical University, Huhhot, 010050, China
hDepartment of Biology, Southern University of Science and Technology, Shenzhen, 518055, China
iGuangzhou Women and Children's Medical Center, Guangzhou, 510623, China
jDepartment of Radiology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
kExperimental and Clinical Research Center (ECRC), A Joint Cooperation Between the Charité Medical Faculty and the Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association (MDC), Lindenberger Weg.80, Berlin, 13125, Germany
lDepartment of Paediatric Medicine Division of Endocrinology, Sidra Medical & Research Center, OPC, Doha, C6-337, Qatar
mMedi-X Institute, SUSTec Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen, 518055, China
More InformationCorresponding author: E-mail address: jingjing.zhang@live.com (Jingjing Zhang);E-mail address: maolian@mdc-berlin.de (Maolian Gong)
Publish Date:2020-10-25
Abstract
Abstract
Congenital hearing loss is a common disorder worldwide. Heterogeneous gene variation accounts for approximately 20–25% of such patients. We investigated a five-generation Chinese family with autosomal-dominant nonsyndromic sensorineural hearing loss (SNHL). No wave was detected in the pure-tone audiometry, and the auditory brainstem response was absent in all patients. Computed tomography of the patients, as well as of two sporadic SNHL cases, showed bilateral inner ear anomaly, cochlear maldevelopment, absence of the osseous spiral lamina, and an enlarged vestibular aqueduct. Such findings were absent in nonaffected persons. We used linkage analysis and exome sequencing and uncovered a heterozygous missense mutation in the PI4KB gene (p.Gln121Arg) encoding phosphatidylinositol 4-kinase β (PI4KB) from the patients in this family. In addition, 3 missense PI4KB (p.Val434Gly, p.Glu667Lys, and p.Met739Arg) mutations were identified in five patients with nonsyndromic SNHL from 57 sporadic cases. No such mutations were present within 600 Chinese controls, the 1000 genome project, gnomAD, or similar databases. Depleting pi4kb mRNA expression in zebrafish caused inner ear abnormalities and audiosensory impairment, mimicking the patient phenotypes. Moreover, overexpression of 4 human missensePI4KB mutant mRNAs in zebrafish embryos resulted in impaired hearing function, suggesting dominant-negative effects. Taken together, our results reveal that PI4KB mutations can cause SNHL and inner ear malformation. PI4KB should be included in neonatal deafness screening.Keywords: Congenital sensorineural hearing loss,
Inner ear malformation,
Phosphatidylinositol 4-kinase β,
Mutations,
Zebrafish
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http://www.jgenetgenomics.org/article/exportPdf?id=4ed2e548-d0b7-49eb-9eea-e4847e55ad19&language=en
