Abstract

BackgroundThe fimbrin protein family contains a variety of proteins, of which Plastin1 (PLS1) is an important member. The latest researches show that variations in the coding region of PLS1 gene is related to the development of deafness. However, it remains unknown about the molecular mechanism of deafness caused by PLS1 gene variants. Methodswhole exome sequencing was performed on the affected family members and healthy ones to identify the pathogenic variants, followed by sanger sequencing. Minigene assay was conducted to investigate the impact of the variant on PLS1 mRNA splicing. The pathogenicity of the variant was further investigated in zebrafish. RNA-sequencing (RNA-seq) was done for analyzing the dysregulated downstream signaling pathways caused by knockdown of PLS1 expression. ResultsWe identified a novel variant PLS1 c.981+1G>A in a large Chinese family with hearing loss and demonstrated that the variant is responsible for the occurrence of hearing loss by inducing Exon8 skipping or deletion of Exon8 (47bp). The variant caused abnormal inner ear phenotypes, characterized by decreased mean otolith distance, anterior otolith diameter, posterior otolith diameter, and cochlear diameter, swimming speed and distance in zebrafish. Furthermore, silencing PLS1 expression significantly upregulated genes in the PI3K-Akt signaling pathway, including Col6a3, Spp1, Itgb3 and Hgf. ConclusionsPLS1 c.981+1G>A is a novel pathogenic variant for hearing loss by inducing Exon8 skipping or deletion of Exon8 (47bp). Up-regulation of the PI3K-Akt signaling pathway plays an important role in the pathogenesis of PLS-1 gene.