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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2016, Vol. 10 Issue (3) : 250-257     DOI: 10.1007/s11684-016-0454-y
Alternative splicing of inner-ear-expressed genes
Yanfei Wang1,Yueyue Liu1,Hongyun Nie1,Xin Ma2,Zhigang Xu1,*()
1. Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Jinan 250100, China
2. School of Control Science and Engineering, Shandong University, Jinan 250061, China
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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 Ca2+-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.

Keywords alternative splicing      inner ear      hearing loss      hair cells     
Corresponding Authors: Zhigang Xu   
Just Accepted Date: 14 June 2016   Online First Date: 08 July 2016    Issue Date: 30 August 2016
URL:     OR
Fig.1  Schematic drawing of inner-ear-specific splicing of Cadherin 23 (Cdh23). (A) CDH23 contains a signal peptide (SP), 27 extracellular cadherin (EC) repeats, a transmembrane (TM) domain, and a cytoplasmic segment. Exon 68 encodes for part of the cytoplasmic segment. Alternative splicing of exon 68 produces two splice variants, CDH23(+68) and CDH23(−68). (B) Cdh23(−68) is expressed in multiple tissue, including the inner ear, tongue, eye, testis, cerebrum and cerebellum. By contrast, Cdh23(+68) is only detected in the inner ear.
Gene name Description Characteristics related to alternative splicing Disease caused by gene mutation Hearing-related phenotypes in knockout/mutant mice References
CDH23 Untypical cadherin 23 Exon 68 is subject to inner-ear-specific splicing DFNB12, USH1D Tip-link interruption, hair cell degeneration, and hearing loss [1827]
KCNMA1 Calcium-activated potassium channel, subfamily M α 1 Alternatively spliced along the tonotopic axis in the cochlea Not reported OHC degeneration and progressive hearing loss [3945]
KCNQ4 Voltage-gated potassium channel, subfamily Q member 4 Alternatively spliced along the tonotopic axis in the cochlea DFNA2 OHC degeneration and progressive hearing loss [4649]
SRRM4 Splicing factor, serine/arginine repetitive matrix 4 Alternative splicing factor Not reported IHC degeneration and hearing loss [8,5362]
SFSWAP Splicing factor, suppressor of white-apricot family Alternative splicing factor Not reported OHC and SC loss, ectopic IHC, cochlear shortening, and hearing loss [6369]
Tab.1  Genes involved in or subject to alternative splicing in the inner ear
Fig.2  Schematic drawing of tonotopic alternative splicing of chicken kcnma1 mRNA, which encodes for BK channel a subunit. (A) Proposed membrane topology of BK channel a subunit. There are at least 7 alternative splicing sites in chicken kcnma1 mRNA, and the alternative splicing showed here involves the inclusion of 12 nucleotides, which encodes 4 amino acids (SRKR) [40]. The SRKR insertion site is denoted by an arrow. (B) Chicken Kcnma1 mRNA is subject to alternative splicing along the basilar papilla, which is the avian equivalent of the mammalian organ of Corti. Hair cells are arranged in a tonotopic gradient along the basilar papilla. Low-frequency sounds are detected at the apical end of the basilar papilla, and high-frequency sounds are detected at the basal end of the basilar papilla. The different expression levels of two splice variants (with or without SRKR insertion) of kcnma1 mRNA are observed along the basilar papilla.
Fig.3  Schematic drawing of the domain architecture of some SR proteins. SRSF1, also called SF2 or ASF, is a prototypical SR protein, which contains two RNA recognition motifs (RRM) and one serine/arginine-rich domain (RS). SRRM4 and SFSWAP are two splicing factors whose mutations cause hearing loss in mice.
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