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

Abstract

CaBPs are a family of Ca(2+)-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 Ca(2+) signaling through effectors such as voltage-gated Ca(v) Ca(2+) channels. In this study, we identified a splice-site mutation (c.637+1G>T) in Ca(2+)-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 Ca(2+) binding in isothermal titration calorimetry and less potent regulation of Ca(v)1.3 Ca(2+) channels. We show that genetic defects in CABP2 cause moderate-to-severe sensorineural hearing impairment. The mutation might cause a hypofunctional CaBP2 defective in Ca(2+) sensing and effector regulation in the inner ear.

Ca 2+ -binding protein 2 inhibits Ca 2+ -channel inactivation in mouse inner hair cells

“…We postulate that both alleles disrupt CaBP2 function and assume that the c.466G > T mutation compromises CaBP2 function via nonsense-mediated mRNA decay. The tone audiograms were comparable between both mutant CABP2 genotypes (35). However, unlike in our previous report, a transitory evoked otoacoustic emission (TEOAE) was observed in subject III:1 in the course of clinical examination at the age of 4 y (subject III:3 was not tested for TEOAE).…”

“…Moreover, DFNB93 might arise from impaired excitation-secretion coupling due to a depolarized shift of Ca 2+ -channel activation as was postulated for CABP4 disruption in photoreceptors in congenital stationary night blindness (36). Finally, CaBP2 reduced the Ca 2+ -current density in HEK293-T cells, which was not found with the truncated CaBP2 reported to cause DFNB93 (35). Therefore, excess Ca 2+ influx and glutamate release might cause excitotoxic synapse loss [excitotoxicity during loud noise (37)] in DFNB93.…”

“…We did not observe obvious deficits outside the auditory system, which is in keeping with the rather hair cell-specific expression of CaBP2 and the clinical findings in DFNB93 (this study and refs. 35,44). Elevated thresholds, reduced amplitudes and prolonged latencies of ABRs, of which the first peak reports the synchronous activation of SGNs, are likely accounted by the reduced firing rates and delayed, as well as more variable, spike timing of SGNs at sound onset.…”

“…18,19,34). CaBPs have been shown to confer both the negative activation (36) and the noninactivating (18,19,35,52) phenotypes to Ca V channels in HEK293 cells. Our HEK293 cell study demonstrates that CaBP2 can potently shift Ca V 1.3 activation to more hyperpolarized potentials and inhibit Ca V 1.3 channel inactivation.…”

“…1C). This feature led to screening for mutations in the TECTA and CABP2 genes, which are known to cause an audiometric phenotype similar the one observed in the subjects (35,38).…”