|
| Status |
Public on Sep 01, 2017 |
| Title |
ESRP1 mutations cause hearing loss due to defects in alternative splicing that disrupt cochlear development |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
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 consistent with impaired ESRP1 function. To determine how mutations in ESRP1 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 inner ear development and auditory function. In particular, 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 novel cause of SNHL and demonstrate the complex interplay between alternative splicing, inner ear development, and auditory function.
|
| |
|
| Overall design |
3 biological replicates of whole E16.5 cochlear epithelium from individual Esrp1+/+ (Control) and Esrp1-/- (E1-KO) embryos (2 cochlea pooled from each embryo) were analyzed by RNA-seq
|
| |
|
| Contributor(s) |
Rohacek AM, Bebee TW, Tilton RK, Radens CM, Barash Y, Germiller JA, Krantz ID, Carstens RP, Epstein DJ |
| Citation(s) |
29107558 |
| |
| Submission date |
Dec 02, 2016 |
| Last update date |
May 15, 2019 |
| Contact name |
Douglas J Epstein |
| E-mail(s) |
epsteind@mail.med.upenn.edu
|
| Phone |
2155734810
|
| Organization name |
University of Pennsylvania
|
| Department |
Genetics
|
| Lab |
Douglas J. Epstein
|
| Street address |
415 Curie Blvd
|
| City |
Philadelphia |
| State/province |
Pennsylvania |
| ZIP/Postal code |
19104 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
|
| Samples (12)
|
|
| Relations |
| BioProject |
PRJNA356069 |
| SRA |
SRP094495 |
Less...
More...