Exonic mutations and exon skipping: Lessons learned from DFNA5

Kevin T Booth; Hela Azaiez; Kimia Kahrizi; Donghong Wang; Yuzhou Zhang; Kathy Frees; Carla Nishimura; Hossein Najmabadi; Richard J Smith

doi:10.1002/humu.23384

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Exonic mutations and exon skipping: Lessons learned from DFNA5

Journal article

Open access

Peer reviewed

Exonic mutations and exon skipping: Lessons learned from DFNA5

Kevin T Booth, Hela Azaiez, Kimia Kahrizi, Donghong Wang, Yuzhou Zhang, Kathy Frees, Carla Nishimura, Hossein Najmabadi and Richard J Smith

Human mutation, Vol.39(3), pp.433-440

03/2018

DOI: 10.1002/humu.23384

PMCID: PMC5805621

PMID: 29266521

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Abstract

Dysregulation of splicing is a common factor underlying many inherited diseases including deafness. For one deafness‐associated gene, DFNA5, perturbation of exon 8 splicing results in a constitutively active truncated protein. To date, only intronic mutations have been reported to cause exon 8 skipping in patients with DFNA5‐related deafness. In five families with postlingual progressive autosomal dominant non‐syndromic hearing loss, we employed two next‐generation sequencing platforms—OtoSCOPE and whole exome sequencing—followed by variant filtering and prioritization based on both minor allele frequency and functional consequence using a customized bioinformatics pipeline to identify three novel and two recurrent mutations in DFNA5 that segregated with hearing loss in these families. The three novel mutations are all missense variants within exon 8 that are predicted computationally to decrease splicing efficiency or abolish it completely. We confirmed their functional impact in vitro using mini‐genes carrying each mutant DFNA5 exon 8. In so doing, we present the first exonic mutations in DFNA5 to cause deafness, expand the mutational spectrum of DFNA5‐related hearing loss, and highlight the importance of assessing the effect of coding variants on splicing. DFNA5‐related hearing loss is caused by skipping of exon 8. Novel and previously described pathogenic variants are shown aligned to DFNA5 exon 8 and its flanking introns, with novel variants on the bottom and previously described variants on the top. The two previously described variants underlined in italics also reported in this study. The predicted binding sites of splicing factors are altered by the novel exonic variants, with values in the parentheses showing the predicted splicing signal for the wild‐type sequence (black) and the mutant sequence (red).

Deafness

RNA‐splicing

exon‐skipping

non‐syndromic hearing loss

DFNA5

Details

Title: Subtitle: Exonic mutations and exon skipping: Lessons learned from DFNA5
Creators: Kevin T Booth - University of Iowa
Hela Azaiez - University of Iowa
Kimia Kahrizi - University of Social Welfare and Rehabilitation Sciences
Donghong Wang - University of Iowa
Yuzhou Zhang - University of Iowa
Kathy Frees - University of Iowa
Carla Nishimura - University of Iowa
Hossein Najmabadi - University of Social Welfare and Rehabilitation Sciences
Richard J Smith - University of Iowa
Resource Type: Journal article
Publication Details: Human mutation, Vol.39(3), pp.433-440
DOI: 10.1002/humu.23384
PMID: 29266521
PMCID: PMC5805621
NLM abbreviation: Hum Mutat
ISSN: 1059-7794
eISSN: 1098-1004
Number of pages: 8
Grant note: National Institute on Deafness and Other Communication Disorders (R01s DC003544; DC002842; DC012049) Iran National Science Foundation (950100)
Language: English
Date published: 03/2018
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
Record Identifier: 9984006491602771

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