Hearing loss is a complex disorder caused by both genetic and environmental factors. Previously, mutations in CIB2 have been identified as a common cause of genetic hearing loss in Pakistani and Turkish populations. Here we report a novel (c.556C>T; p.(Arg186Trp)) transition mutation in the CIB2 gene identified through whole exome sequencing (WES) in a Caribbean Hispanic family with non-syndromic hearing loss. CIB2 belongs to the family of calcium-and integrin-binding (CIB) proteins. The carboxy-termini of CIB proteins are associated with calcium binding and intracellular signaling. The p.(Arg186Trp) mutation is localized within predicted type II PDZ binding ligand at the carboxy terminus. Our ex vivo studies revealed that the mutation did not alter the interactions of CIB2 with Whirlin, nor its targeting to the tips of hair cell stereocilia. However, we found that the mutation disrupts inhibition of ATP-induced Ca2+ responses by CIB2 in a heterologous expression system. Our findings support p.(Arg186Trp) mutation as a cause for hearing loss in this Hispanic family. In addition, it further highlights the necessity of the calcium binding property of CIB2 for normal hearing.
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This study was partially sponsored by the National Institute on Deafness and Other Communication Disorders (NIDCD/NIH) research grants R01 DC012564 to Z.M.A. and R01 DC011803 to S.R. Support for this work was provided by a gift from the Department of Pediatrics at Montefiore Medical Center and the Human Genetics Program in the Department of Genetics at Albert Einstein College of Medicine (K. P. and B.E.M.). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.
Patel, Kunjan; Giese, Arnaud P.; Grossheim, J. M.; Hegde, Rashima S.; Delio, Maria; Samanich, Joy; Riazuddin, Saima; Frolenkov, Gregory I.; Cai, Jinlu; Ahmed, Zubair M.; and Morrow, Bernice E., "A Novel C-Terminal CIB2 (Calcium and Integrin Binding Protein 2) Mutation Associated with Non-Syndromic Hearing Loss in a Hispanic Family" (2015). Physiology Faculty Publications. 72.