title: Novel and recurrent CIB2 variants, associated with nonsyndromic deafness, do not affect calcium buffering and localization in hair cells.
abstract: Variants in CIB2 can underlie either Usher syndrome type I (USH1J) or nonsyndromic hearing impairment (NSHI) (DFNB48). Here, a novel homozygous missense variant c.196C>T and compound heterozygous variants, c.[97C>T];[196C>T], were found, respectively, in two unrelated families of Dutch origin. Besides, the previously reported c.272 T>C functional missense variant in CIB2 was identified in two families of Pakistani origin. The missense variants are demonstrated not to affect subcellular localization of CIB2 in vestibular hair cells in ex vivo expression experiments. Furthermore, these variants do not affect the ATP-induced calcium responses in COS-7 cells. However, based on the residues affected, the variants are suggested to alter αIIβ integrin binding. HI was nonsyndromic in all four families. However, deafness segregating with the c.272T>C variant in one Pakistani family is remarkably less severe than that in all other families with this mutation. Our results contribute to the insight in genotype-phenotype correlations of CIB2 mutations.
authors.affiliation: Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen, The Netherlands.|Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Celia Zazo
authors.initials: CZ
authors.lastname: Seco
authors.affiliation: Department of Otorhinolaryngology Head & Neck Surgery, College of Medicine, University of Maryland, Baltimore, MD, USA.
authors.forename: Arnaud P
authors.initials: AP
authors.lastname: Giese
authors.affiliation: COMSATS Institute of Information Technology, Islamabad, Pakistan.
authors.forename: Sobia
authors.initials: S
authors.lastname: Shafique
authors.affiliation: Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen, The Netherlands.|Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Margit
authors.initials: M
authors.lastname: Schraders
authors.affiliation: Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Anne M M
authors.initials: AM
authors.lastname: Oonk
authors.affiliation: Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA.
authors.forename: Mike
authors.initials: M
authors.lastname: Grossheim
authors.affiliation: Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen, The Netherlands.|Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: Oostrik
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Strom
authors.affiliation: Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Hegde
authors.affiliation: Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen, The Netherlands.|Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Erwin
authors.initials: E
authors.lastname: van Wijk
authors.affiliation: Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA.
authors.forename: Gregory I
authors.initials: GI
authors.lastname: Frolenkov
authors.affiliation: COMSATS Institute of Information Technology, Islamabad, Pakistan.
authors.forename: Maleeha
authors.initials: M
authors.lastname: Azam
authors.affiliation: Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Helger G
authors.initials: HG
authors.lastname: Yntema
authors.affiliation: Department of Otorhinolaryngology/Head and Neck Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Rolien H
authors.initials: RH
authors.lastname: Free
authors.affiliation: Department of Otorhinolaryngology Head & Neck Surgery, College of Medicine, University of Maryland, Baltimore, MD, USA.
authors.forename: Saima
authors.initials: S
authors.lastname: Riazuddin
authors.affiliation: Department of Clinical Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Joke B G M
authors.initials: JB
authors.lastname: Verheij
authors.affiliation: Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Admiraal
authors.affiliation: COMSATS Institute of Information Technology, Islamabad, Pakistan.|Al-Nafees Medical College & Hospital, Isra University, Islamabad, Pakistan.
authors.forename: Raheel
authors.initials: R
authors.lastname: Qamar
authors.affiliation: Department of Otorhinolaryngology Head & Neck Surgery, College of Medicine, University of Maryland, Baltimore, MD, USA.
authors.forename: Zubair M
authors.initials: ZM
authors.lastname: Ahmed
authors.affiliation: Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen, The Netherlands.|Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Hannie
authors.initials: H
authors.lastname: Kremer
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002522:Chlorocebus aethiops; D003638:Deafness / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006198:Hair Cells, Auditory / Q000378:metabolism*; D006801:Humans; D038982:Integrin alpha2beta1 / Q000378:metabolism; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D011485:Protein Binding
chemical_list: C577150:CIB2 protein, human; D002135:Calcium-Binding Proteins; D038982:Integrin alpha2beta1; D002118:Calcium