title: A Novel C-Terminal CIB2 (Calcium and Integrin Binding Protein 2) Mutation Associated with Non-Syndromic Hearing Loss in a Hispanic Family.
abstract: 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.
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, New York, United States of America.
authors.forename: Kunjan
authors.initials: K
authors.lastname: Patel
authors.affiliation: Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland, United States of America.
authors.forename: Arnaud P
authors.initials: AP
authors.lastname: Giese
authors.affiliation: Department of Physiology, College of Medicine, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: J M
authors.initials: JM
authors.lastname: Grossheim
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Centre Cincinnati, Ohio, United States of America.
authors.forename: Rashmi S
authors.initials: RS
authors.lastname: Hegde
authors.forename: Rashima S
authors.initials: RS
authors.lastname: Hegde
authors.affiliation: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, United States of America.
authors.forename: Maria
authors.initials: M
authors.lastname: Delio
authors.affiliation: Department of Pediatrics (Clinical Genetics), Albert Einstein College of Medicine; Montefiore Medical Center, Bronx, New York, United States of America.
authors.forename: Joy
authors.initials: J
authors.lastname: Samanich
authors.affiliation: Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland, United States of America.
authors.forename: Saima
authors.initials: S
authors.lastname: Riazuddin
authors.affiliation: Department of Physiology, College of Medicine, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Gregory I
authors.initials: GI
authors.lastname: Frolenkov
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, New York, United States of America.
authors.forename: Jinlu
authors.initials: J
authors.lastname: Cai
authors.affiliation: Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland, United States of America.
authors.forename: Zubair M
authors.initials: ZM
authors.lastname: Ahmed
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, New York, United States of America.
authors.forename: Bernice E
authors.initials: BE
authors.lastname: Morrow
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002522:Chlorocebus aethiops; D059472:Exome / Q000235:genetics; D005260:Female; D057809:HEK293 Cells; D034381:Hearing Loss / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006630:Hispanic or Latino / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008958:Models, Molecular; D020125:Mutation, Missense; D009218:Myosins / Q000378:metabolism; D010375:Pedigree; D017433:Protein Structure, Secondary; D059547:Stereocilia / Q000378:metabolism
chemical_list: C577150:CIB2 protein, human; D002135:Calcium-Binding Proteins; D008565:Membrane Proteins; C477219:WHRN protein, human; D009218:Myosins; D002118:Calcium