Alternative splicing of inner-ear-expressed genes

Abstract

Alternative splicing plays a fundamental role in the development and physiological function of the inner ear. Inner-ear-specific gene splicing is necessary to establish the identity and maintain the function of the inner ear. For example, exon 68 of Cadherin 23 (Cdh23) gene is subject to inner-ear-specific alternative splicing, and as a result, Cdh23(+ 68) is only expressed in inner ear hair cells. Alternative splicing along the tonotopic axis of the cochlea contributes to frequency tuning, particularly in lower vertebrates, such as chickens and turtles. Differential splicing of Kcnma1, which encodes for the α subunit of the Ca(2+)-activated K(+) channel (BK channel), has been suggested to affect the channel gating properties and is important for frequency tuning. Consequently, deficits in alternative splicing have been shown to cause hearing loss, as we can observe in Bronx Waltzer (bv) mice and Sfswap mutant mice. Despite the advances in this field, the regulation of alternative splicing in the inner ear remains elusive. Further investigation is also needed to clarify the mechanism of hearing loss caused by alternative splicing deficits.

Angulin proteins ILDR1 and ILDR2 regulate alternative pre-mRNA splicing through binding to splicing factors TRA2A, TRA2B, or SRSF1

“…During alternative splicing, the exons of pre-mRNAs are spliced together in different arrangements to give rise to distinct mature mRNAs, which ultimately produces structurally and functionally distinct protein variants 10 . Alternative splicing deficits cause various types of disease including hearing loss 11 , 12 . At present, two splicing factors have been identified to play important roles in the inner ear, namely SRRM4 and SFSWAP 13 , 14 , both of which belong to SR protein family.…”

Signaling in the Auditory System: Implications in Hair Cell Regeneration and Hearing Function

“…In other words, hair bundle deflection generates a force by pulling on tip‐link proteins connecting adjacent stereocilia. Tip‐links are composed of cadherin‐23 (Cdh23) and protocadherin‐15 (Pcdh15), both non‐conventional cadherins, which form the upper and the lower part of these links, respectively (Pepermans and Petit, ; Grati et al, ; Wang et al, ). The MET currents decline during steady stimuli; this is termed adaptation and ensures they always work within the most sensitive part of their operating range, responding best to rapidly changing (sound) stimuli (Marcotti et al, ).…”

Inherited Retinal Disease Therapies Targeting Precursor Messenger Ribonucleic Acid

“…Mutation-induced missplicing of exon 2a of BBS8 was later shown to produce a frameshift mutation in photoreceptors, but not in other cell types that normally exclude this exon [51]. Other genes that undergo alternative splicing, such as MYO7A [52], CDH23 [53], USH1C [54], also play an important role in isolated retinal dystrophy or syndromic disease.…”