期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 91, 期 4, 页码 636-645出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2012.08.018
关键词
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资金
- University of Antwerp
- State of Lower Saxony through the Audiologie Initiative Niedersachsen program
- Federal Ministry for Research and Technology through the Bernstein Center for Computational Neuroscience Gottingen [01GQ1005A]
- German Research Foundation [MO896/3-1]
- Shahrekord University of Medical Sciences
- National Institutes of Health [R01 DC009433, R01 HL087120, R01 EY020850]
- Carver Research Program of Excellence
- Oticon Foundation [09-3742]
- ZonMW [40-00812-98-09047]
CaBPs are a family of Ca2+-binding proteins related to calmodulin and are localized in the brain and sensory organs, including the retina and cochlea. Although their physiological roles are not yet fully elucidated, CaBPs modulate Ca2+ signaling through effectors such as voltage-gated Ca-v Ca2+ channels. In this study, we identified a splice-site mutation (c.637+1G>T) in Ca2+-binding protein 2 (CABP2) in three consanguineous Iranian families affected by moderate-to-severe hearing loss. This mutation, most likely a founder mutation, probably leads to skipping of exon 6 and premature truncation of the protein (p.Phe164Serfs(star)4). Compared with wild-type CaBP2, the truncated CaBP2 showed altered Ca2+ binding in isothermal titration calorimetry and less potent regulation of Ca(v)1.3 Ca2+ channels. We show that genetic defects in CABP2 cause moderate-to-severe sensorineural hearing impairment. The mutation might cause a hypofunctional CaBP2 defective in Ca2+ sensing and effector regulation in the inner ear.
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