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ESRP1 Mutations Cause Hearing Loss due to Defects in Alternative Splicing that Disrupt Cochlear Development.

Developmental cell | Nov 6, 2017

Alternative splicing contributes to gene expression dynamics in many tissues, yet its role in auditory development remains unclear. We performed whole-exome sequencing in individuals with sensorineural hearing loss (SNHL) and identified pathogenic mutations in Epithelial Splicing-Regulatory Protein 1 (ESRP1). Patient-derived induced pluripotent stem cells showed alternative splicing defects that were restored upon repair of an ESRP1 mutant allele. To determine how ESRP1 mutations cause hearing loss, we evaluated Esrp1-/- mouse embryos and uncovered alterations in cochlear morphogenesis, auditory hair cell differentiation, and cell fate specification. Transcriptome analysis revealed impaired expression and splicing of genes with essential roles in cochlea development and auditory function. Aberrant splicing of Fgfr2 blocked stria vascularis formation due to erroneous ligand usage, which was corrected by reducing Fgf9 gene dosage. These findings implicate mutations in ESRP1 as a cause of SNHL and demonstrate the complex interplay between alternative splicing, inner ear development, and auditory function.

Pubmed ID: 29107558 RIS Download

Mesh terms: Alternative Splicing | Animals | Cell Differentiation | Cochlea | Hearing Loss | Mice, Knockout | Mutation | RNA-Binding Proteins

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Associated grants

  • Agency: NIA NIH HHS, Id: R01 AG046544
  • Agency: NHGRI NIH HHS, Id: U01 HG006546
  • Agency: NIDCD NIH HHS, Id: R01 DC006254
  • Agency: NIDCR NIH HHS, Id: R01 DE024749
  • Agency: NIGMS NIH HHS, Id: R01 GM128096
  • Agency: NIGMS NIH HHS, Id: T32 GM008216
  • Agency: NIDCD NIH HHS, Id: F31 DC014647

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Hereditary Hearing Loss Homepage

Overview of the genetics of hereditary hearing impairment for researchers and clinicians. The site lists data and references for all known gene localizations and identifications for nonsyndromic hearing impairment, and several for syndromic hearing loss. For syndromic hearing impairment, only a few of the most frequent forms are covered. An atlas of cochlea with genes listed can be accessed from this site.

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RUM

An alignment, junction calling, and feature quantification pipeline specifically designed for Illumina RNA-Seq data.

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Software performing alignment of high-throughput RNA-seq data. STAR is based on a previously undescribed RNA-seq alignment algorithm that uses sequential maximum mappable seed search in uncompressed suffix arrays followed by seed clustering and stitching procedure.

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IMPC

Center that produces knockout mice and carries out high-throughput phenotyping of each line in order to determine the function of every gene in the mouse genome. These mice will be preserved in repositories and made available to the scientific community representing a valuable resource for basic scientific research as well as generating new models for human diseases.

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