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A novel PLS1 c.981+1G>A variant causes autosomal-dominant hereditary hearing loss in a family |
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| Authors: | Liangpu Xu Xinrui Wang Jia Li Lingji Chen Haiwei Wang Shiyi Xu Yanhong Zhang Wei Li Pengcheng Yao Meihua Tan Si Zhou Meihuan Chen Yali Pan Xuemei Chen Xiaolan Chen Yunliang Liu Na Lin Hailong Huang Hua Cao |
| Institution: | 1. Medical Genetic Diagnosis and Therapy Center of Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Provincial Key Laboratory of Prenatal Diagnosis and Birth Defect, Fuzhou, China;2. Medical Genetic Diagnosis and Therapy Center of Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Provincial Key Laboratory of Prenatal Diagnosis and Birth Defect, Fuzhou, China
Medical Research Center, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, China NHC Key Laboratory of Technical Evaluation of Fertility Regulation for Non-human Primates, Fujian Maternity and Child Health Hospital, Fuzhou, China;3. BGI Genomics, BGI-Shenzhen, Shenzhen, China Hebei Industrial Technology Research Institute of Genomics in Maternal & Child Health, Shijiazhuang BGI Genomics Co., Ltd., Shijiazhuang, China;4. Medical Genetic Diagnosis and Therapy Center of Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Provincial Key Laboratory of Prenatal Diagnosis and Birth Defect, Fuzhou, China Medical Research Center, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, China;5. The First Clinical Medical College, Guangxi Medical University, Nanning, China;6. Department of Laboratory Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China;7. BGI Genomics, BGI-Shenzhen, Shenzhen, China;8. BGI Genomics, BGI-Shenzhen, Shenzhen, China Hebei Industrial Technology Research Institute of Genomics in Maternal & Child Health, Shijiazhuang BGI Genomics Co., Ltd., Shijiazhuang, China College of Life Sciences, University of Chinese Academy of Sciences, China;9. Department of Laboratory Medicine, Medical Technology and Engineering College of Fujian Medical University, Fuzhou, China;10. Otolaryngological Department of Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, China;11. Medical Research Center, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, China |
| Abstract: | The fimbrin protein family contains a variety of proteins, among which Plastin1 (PLS1) is an important member. According to recent studies, variations in the coding region of the PLS1 gene are associated with the development of deafness. However, the molecular mechanism of deafness caused by PLS1 gene variants remains unknown. Whole-exome sequencing was performed on hearing-impaired family members and hearing family members to identify pathogenic variants, followed by Sanger sequencing. A minigene assay was conducted to investigate the effect of the variant on PLS1 mRNA splicing. The pathogenicity of the variant was further investigated in zebrafish. RNA-sequencing (RNA-seq) was performed to analyze the dysregulation of downstream signaling pathways caused by knockdown of PLS1 expression. We identified a novel variant, PLS1 c.981+1G>A, in a large Chinese family with hearing loss and showed that the variant is responsible for the occurrence of hearing loss by inducing exon 8 skipping. The variant caused abnormal inner ear phenotypes, characterized by decreases in the mean otolith distance, anterior otolith diameter, posterior otolith diameter, cochlear diameter, and swimming speed and distance in zebrafish. Furthermore, silencing PLS1 expression significantly upregulated the expression of genes in the PI3K-Akt signaling pathway, including Col6a3, Spp1, Itgb3 and hepatocyte growth factor (Hgf). PLS1 c.981+1G>A is a novel pathogenic variant causing hearing loss by inducing exon 8 skipping. Upregulation of the expression of genes in the PI3K-Akt signaling pathway plays an important role in the pathogenesis caused by variants in the PLS1 gene. |
| Keywords: | hearing loss PI3K-Akt signaling pathway PLS1 RNA splicing |