Novel and recurrent CIB2 variants, associated with nonsyndromic deafness, do not affect calcium buffering and localization in hair cells

Eur J Hum Genet. 2016 Apr;24(4):542-9. doi: 10.1038/ejhg.2015.157.

Celia Zazo Seco ¹ ², Arnaud P Giese ³, Sobia Shafique ⁴, Margit Schraders ¹ ², Anne M M Oonk ¹, Mike Grossheim ⁵, Jaap Oostrik ¹ ², Tim Strom ⁶, Rashmi Hegde ⁷, Erwin van Wijk ¹ ², Gregory I Frolenkov ⁵, Maleeha Azam ⁴, Helger G Yntema ² ⁸, Rolien H Free ⁹, Saima Riazuddin ³, Joke B G M Verheij ¹⁰, Ronald J Admiraal ¹, Raheel Qamar ⁴ ¹¹, Zubair M Ahmed ³, Hannie Kremer ¹ ² ⁸

Affiliations

1 Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen, The Netherlands.
2 Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
3 Department of Otorhinolaryngology Head & Neck Surgery, College of Medicine, University of Maryland, Baltimore, MD, USA.
4 COMSATS Institute of Information Technology, Islamabad, Pakistan.
5 Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA.
6 Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
7 Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
8 Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
9 Department of Otorhinolaryngology/Head and Neck Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
10 Department of Clinical Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
11 Al-Nafees Medical College & Hospital, Isra University, Islamabad, Pakistan.

PMID: 26173970 DOI: 10.1038/ejhg.2015.157

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.

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