Phosphatidylinositol 4-kinase β mutations cause nonsyndromic sensorineural deafness and inner ear malformation |
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| Institution: | 1. Clinical Medicine Research Center, Affiliated Hospital of Inner Mongolia Medical University, Huhhot, 010050, China;2. Affiliated Hospital of Guangdong Medical University & Key Laboratory of Zebrafish Model for Development and Disease of Guangdong Medical University, Zhanjiang, 524001, China;3. Marine Medical Research Institute of Guangdong Zhanjiang, Zhanjiang, 524023, China;4. Genomic Medicine Programme, UCL Institute of Child Health and Great Ormond Street Hospital for Children, 30 Guilford Street, London, WC1N 1EH, UK;5. Max-Delbrueck-Center for Molecular Medicine (MDC), Robert-Roessle-Str.10, Berlin, 13125, Germany;6. Department of Radiology, Affiliated Hospital of Inner Mongolia Medical University, Huhhot, 010050, China;7. Affiliated People Hospital of Inner Mongolia Medical University, Huhhot, 010050, China;8. Department of Biology, Southern University of Science and Technology, Shenzhen, 518055, China;9. Guangzhou Women and Children''s Medical Center, Guangzhou, 510623, China;10. Department of Radiology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China;11. Experimental 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;12. Department of Paediatric Medicine Division of Endocrinology, Sidra Medical & Research Center, OPC, Doha, C6-337, Qatar;13. Medi-X Institute, SUSTec Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen, 518055, China;1. Department of Pediatrics, Guangzhou Women and Children''s Medical Center, Guangzhou Medical University, Guangzhou, China;2. Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, China National Center for Bioinformation, Beijing, 101300, China;3. University of Chinese Academy of Sciences, Beijing, 100049, China;4. Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China;1. Department of Genetics, Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai and Shanghai Academy of Science and Technology, Shanghai 200025, China;2. Department of Cardiology, Changhai Hospital, The Second Military Medical University, Shanghai 200433, China |
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| 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 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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| Keywords: | Congenital sensorineural hearing loss Inner ear malformation Phosphatidylinositol 4-kinase β Mutations Zebrafish |
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