A Mutation in CABP2, Expressed in Cochlear Hair Cells, Causes Autosomal-Recessive Hearing Impairment

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• 作者：Isabelle Schrauwen ; Sarah Helfmann ; Akira Inagaki ; Friederike Predoehl ; Mohammad?Amin Tabatabaiefar ; Maria?Magdalena Picher ; Manou Sommen ; Celia?Zazo Seco ; Jaap Oostrik ; Hannie Kremer ; Annelies Dheedene ; Charlotte Claes ; Erik Fransen ; Morteza?Hashemzadeh Chaleshtori ; Paul Coucke ; Amy Lee ; Tobias Moser ; Guy Van?Camp
• 刊名：The American Journal of Human Genetics
• 出版年：2012
• 出版时间：5 October, 2012
• 年：2012
• 卷：91
• 期：4
• 页码：636-645
• 全文大小：600 K

文摘

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^?4). Compared with wild-type CaBP2, the truncated CaBP2 showed altered Ca²⁺ binding in isothermal titration calorimetry and less potent regulation of Ca_v1.3 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.