A mutation in the Srrm4 gene causes alternative splicing defects and deafness in the Bronx waltzer mouse

Yoko Nakano; Israt Jahan; Gregory Bonde; Xingshen Sun; Michael S Hildebrand; John F Engelhardt; Richard J H Smith; Robert A Cornell; Bernd Fritzsch; Botond Bánfi

doi:10.1371/journal.pgen.1002966

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A mutation in the Srrm4 gene causes alternative splicing defects and deafness in the Bronx waltzer mouse

Journal article

Open access

Peer reviewed

A mutation in the Srrm4 gene causes alternative splicing defects and deafness in the Bronx waltzer mouse

Yoko Nakano, Israt Jahan, Gregory Bonde, Xingshen Sun, Michael S Hildebrand, John F Engelhardt, Richard J H Smith, Robert A Cornell, Bernd Fritzsch and Botond Bánfi

PLoS genetics, Vol.8(10), pp.e1002966-e1002966

2012

DOI: 10.1371/journal.pgen.1002966

PMCID: PMC3464207

PMID: 23055939

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Abstract

Sensory hair cells are essential for hearing and balance. Their development from epithelial precursors has been extensively characterized with respect to transcriptional regulation, but not in terms of posttranscriptional influences. Here we report on the identification and functional characterization of an alternative-splicing regulator whose inactivation is responsible for defective hair-cell development, deafness, and impaired balance in the spontaneous mutant Bronx waltzer (bv) mouse. We used positional cloning and transgenic rescue to locate the bv mutation to the splicing factor-encoding gene Ser/Arg repetitive matrix 4 (Srrm4). Transcriptome-wide analysis of pre-mRNA splicing in the sensory patches of embryonic inner ears revealed that specific alternative exons were skipped at abnormally high rates in the bv mice. Minigene experiments in a heterologous expression system confirmed that these skipped exons require Srrm4 for inclusion into the mature mRNA. Sequence analysis and mutagenesis experiments showed that the affected transcripts share a novel motif that is necessary for the Srrm4-dependent alternative splicing. Functional annotations and protein-protein interaction data indicated that the encoded proteins cluster in the secretion and neurotransmission pathways. In addition, the splicing of a few transcriptional regulators was found to be Srrm4 dependent, and several of the genes known to be targeted by these regulators were expressed at reduced levels in the bv mice. Although Srrm4 expression was detected in neural tissues as well as hair cells, analyses of the bv mouse cerebellum and neocortex failed to detect splicing defects. Our data suggest that Srrm4 function is critical in the hearing and balance organs, but not in all neural tissues. Srrm4 is the first alternative-splicing regulator to be associated with hearing, and the analysis of bv mice provides exon-level insights into hair-cell development.

RNA Precursors - chemistry

Cell Line

Deafness - genetics

Alternative Splicing

Cerebellum - metabolism

Humans

Transcriptome

Molecular Sequence Data

RNA Precursors - genetics

Nerve Tissue Proteins - genetics

Phenotype

Animals

Nucleotide Motifs

Hair Cells, Auditory, Inner - metabolism

Base Sequence

RNA Precursors - metabolism

Mice

Mutation

Transgenes

Gene Order

Cluster Analysis

Disease Models, Animal

Details

Title: Subtitle: A mutation in the Srrm4 gene causes alternative splicing defects and deafness in the Bronx waltzer mouse
Creators: Yoko Nakano - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Israt Jahan
Gregory Bonde
Xingshen Sun
Michael S Hildebrand
John F Engelhardt
Richard J H Smith
Robert A Cornell
Bernd Fritzsch
Botond Bánfi
Resource Type: Journal article
Publication Details: PLoS genetics, Vol.8(10), pp.e1002966-e1002966
DOI: 10.1371/journal.pgen.1002966
PMID: 23055939
PMCID: PMC3464207
NLM abbreviation: PLoS Genet
ISSN: 1553-7390
eISSN: 1553-7404
Publisher: Public Library Science; United States
Grant note: R01DC010152 / NIDCD NIH HHS R01GM067841 / NIGMS NIH HHS P30 DK-54759 / NIDDK NIH HHS R01 DC005590 / NIDCD NIH HHS P30 DK054759 / NIDDK NIH HHS R01 DC010152 / NIDCD NIH HHS
Language: English
Date published: 2012
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; Biology; Radiation Oncology; Craniofacial Anomalies Research Center; Dental Research; Otolaryngology; Internal Medicine
Record Identifier: 9984006355502771

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