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Alterations of the CIB2 calcium- and integrin-binding protein cause Usher syndrome type 1J and nonsyndromic deafness DFNB48

Nature Genetics volume 44, pages 1265–1271 (2012)Cite this article

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An Author Correction to this article was published on 26 August 2025

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Abstract

Sensorineural hearing loss is genetically heterogeneous. Here, we report that mutations in CIB2, which encodes a calcium- and integrin-binding protein, are associated with nonsyndromic deafness (DFNB48) and Usher syndrome type 1J (USH1J). One mutation in CIB2 is a prevalent cause of deafness DFNB48 in Pakistan; other CIB2 mutations contribute to deafness elsewhere in the world. In mice, CIB2 is localized to the mechanosensory stereocilia of inner ear hair cells and to retinal photoreceptor and pigmented epithelium cells. Consistent with molecular modeling predictions of calcium binding, CIB2 significantly decreased the ATP-induced calcium responses in heterologous cells, whereas mutations in deafness DFNB48 altered CIB2 effects on calcium responses. Furthermore, in zebrafish and Drosophila melanogaster, CIB2 is essential for the function and proper development of hair cells and retinal photoreceptor cells. We also show that CIB2 is a new member of the vertebrate Usher interactome.

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Figure 1: Pedigrees of families with USH1J or DFNB48.
Figure 2: CIB2 isoforms, molecular models and functional effects of mutations.
Figure 3: Cib2 localization in hair cells of the mouse organ of Corti and vestibular sensory epithelia.
Figure 4: CIB2 homodimerizes and interacts with whirlin and myosin VIIa.
Figure 5: Suppression of cib2 expression produces developmental defects in zebrafish embryos.
Figure 6: Physiological and morphological changes in Drosophila cib2-deficient retinas.

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Acknowledgements

We thank the families for their participation and cooperation. We also thank G.N. Sarangdhar, R. Rachel, T. Jaworek, V. Ponferrada and K. Gul for technical assistance and R.J. Morell, J. Schultz, D. Drayna, A. Swaroop and A.J. Griffith for critique of the manuscript. We thank T.M. Leisner (University of North Carolina at Chapel Hill) for the generous gift of antibodies to CIB. Genotyping services were provided to S.M.L. by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract (N01-HG-65403) from the US National Institutes of Health (NIH) to Johns Hopkins University. Z.M.A. is a recipient of a Research to Prevent Blindness Career Development Award. This work was also supported by funding from the Higher Education Commission and the Ministry of Science and Technology (Islamabad, Pakistan) to Sheikh Riazuddin and W.A., the International Center for Genetic Engineering and Biotechnology (Trieste, Italy) under project CRP/PAK08-01 contract 08/009 to Sheikh Riazuddin, the Cincinnati Children's Hospital Research Foundation (CCHMC) Intramural Research Funds to Saima Riazuddin and Z.M.A., a National Science Foundation grant (IOS-1050754) to E.K.B., US National Institute on Deafness and Other Communication Disorders (NIDCD/NIH) research grants R01 DC03594 and DC011651 to S.M.L., R01 HL092544 to L.V.P., R01 DC009645 to M.T., R01 DC008861 to G.I.F., R01 DC012564 and R00 DC009287 to Z.M.A., and R01 DC011803 and R01 DC011748 to Saima Riazuddin, and intramural funds from the NIDCD (DC000039-15) to T.B.F.

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Authors and Affiliations

  1. Division of Pediatric Otolaryngology/Head & Neck Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA

    Saima Riazuddin, Arnaud P J Giese, Rizwan Yousaf & Zubair M Ahmed

  2. Division of Pediatric Ophthalmology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA

    Saima Riazuddin, Arnaud P J Giese, David Terrell, Tiffany Cook & Zubair M Ahmed

  3. Department of Otolaryngology, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA

    Saima Riazuddin & Zubair M Ahmed

  4. Department of Ophthalmology, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA

    Saima Riazuddin, Tiffany Cook & Zubair M Ahmed

  5. Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, Rockville, Maryland, USA

    Inna A Belyantseva, Sue Lee & Thomas B Friedman

  6. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA

    Kwanghyuk Lee, Paula B Andrade-Elizondo & Suzanne M Leal

  7. Department of Physiology, University of Kentucky, Lexington, Kentucky, USA

    Artur A Indzhykulian, Ghanshyam P Sinha & Gregory I Frolenkov

  8. Department of Biological Sciences, McMicken College of Arts and Sciences, University of Cincinnati, Cincinnati, Ohio, USA

    Sri Pratima Nandamuri & Elke K Buschbeck

  9. National Center for Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan

    Rizwan Yousaf, Rana A Ali, Saima Anwar & Shaheen N Khan

  10. Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA

    Rashmi S Hegde & Tiffany Cook

  11. Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, Florida, USA

    Asli Sirmaci & Mustafa Tekin

  12. Department of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

    Leslie V Parise

  13. Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan

    Sulman Basit, Muhammad Ansar & Wasim Ahmad

  14. Institute of Biotechnology, Baluchistan University of Information Technology, Quetta, Pakistan

    Abdul Wali

  15. Institute of Biochemistry, University of Baluchistan, Quetta, Pakistan

    Muhammad Ayub

  16. Allama Iqbal Medical College, Lahore, Pakistan

    Javed Akram & Sheikh Riazuddin

  17. University of Lahore, Lahore, Pakistan

    Sheikh Riazuddin

  18. Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan, Pakistan

    Zubair M Ahmed

Authors
  1. Saima Riazuddin
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  2. Inna A Belyantseva
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  3. Arnaud P J Giese
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  8. Ghanshyam P Sinha
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  11. Rashmi S Hegde
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  17. Sulman Basit
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  18. Abdul Wali
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  19. Muhammad Ayub
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  20. Muhammad Ansar
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  21. Wasim Ahmad
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  22. Shaheen N Khan
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  24. Mustafa Tekin
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  25. Sheikh Riazuddin
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  26. Tiffany Cook
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  27. Elke K Buschbeck
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  28. Gregory I Frolenkov
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  29. Suzanne M Leal
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  30. Thomas B Friedman
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  31. Zubair M Ahmed
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Contributions

Z.M.A., Saima Riazuddin and T.B.F. conceived and designed the study. Saima Riazuddin and Z.M.A. performed linkage, RT-PCR and mutational analyses, cloned isoforms and provided bioinformatics evaluations. I.A.B. and S.L. conducted immunocytochemistry and quantification analyses on the inner ears of wild-type and mutant mice, performed transfection assays using sensory epithelial explants and interpreted results. A.P.J.G. performed coimmunoprecipitation assays, immunocytochemistry of CIB2 in retinas and myo7a–mutant mice. K.L. and P.B.A.-E. analyzed linkage data and screened controls. S.B., A.W., M. Ayub, M. Ansar and W.A. enrolled Pakistani families. G.I.F., A.A.I. and G.P.S. performed calcium imaging in COS-7 cells, scanning electron microscopy imaging of zebrafish embryos and recording of microphonic potentials. E.K.B. and S.P.N. designed and conducted ERG studies in flies. R.Y. performed morpholino microinjections, FM1-43 dye uptake experiments, RT-PCR and startle response measurements. T.C. and D.T. generated the cib2-mutant flies and conducted light stress analysis and light microscopy imaging of fly eyes. R.S.H. performed molecular modeling. R.A.A., S.A., J.A., S.N.K. and Sheikh Riazuddin ascertained Pakistani families, obtained clinical data and performed linkage and mutational analyses. L.V.P. provided the Cib1-mutant mice. M.T. and A.S. enrolled the Turkish families and performed linkage analysis. S.M.L. supervised the work at the Baylor College of Medicine, G.I.F. supervised the work at the University of Kentucky, and T.B.F. supervised the work at the NIDCD/NIH and helped with data interpretation. Saima Riazuddin, T.B.F. and Z.M.A. wrote the manuscript; G.I.F., E.K.B., T.C., I.A.B. and S.M.L. edited the manuscript. All authors contributed to the final version of the manuscript.

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Correspondence to Zubair M Ahmed.

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Riazuddin, S., Belyantseva, I., Giese, A. et al. Alterations of the CIB2 calcium- and integrin-binding protein cause Usher syndrome type 1J and nonsyndromic deafness DFNB48. Nat Genet 44, 1265–1271 (2012). https://doi.org/10.1038/ng.2426

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