J Genet Genom. 2020;[Epub] doi:10.1016/j.jgg.2020.07.008
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 non-syndromic sensorineural hearing loss (SNHL). No wave was detected in the pure-tone audiometry and auditory brainstem response (ABR) was absent in all patients. Computerized tomography (CT) in the patients, as well as in two sporadic SNHL cases showed bilateral inner ear anomaly, cochlear mal-development, absence of the osseous spiral lamina, and 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. Additionally, 3 missense PI4KB (p.Val434Gly, p.Glu667Lys, and p.Met739Arg) mutations were identified in five non-syndromic SNHL patients 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 audio-sensory impairment, mimicking the patient phenotypes. Moreover, over-expression of 4 human missense PI4KB 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.
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