Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

Subjects

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

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.

Accession codes

Accessions

NCBI Reference Sequence

Protein Data Bank

References

  1. Ahmad, J. et al. DFNB48, a new nonsyndromic recessive deafness locus, maps to chromosome 15q23-q25.1. Hum. Genet. 116, 407–412 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. Ahmed, Z.M., Riazuddin, S., Khan, S.N., Friedman, P.L. & Friedman, T.B. USH1H, a novel locus for type I Usher syndrome, maps to chromosome 15q22–23. Clin. Genet. 75, 86–91 (2009).

    Article  CAS  PubMed  Google Scholar 

  3. Adzhubei, I.A. et al. A method and server for predicting damaging missense mutations. Nat. Methods 7, 248–249 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Schwarz, J.M., Rodelsperger, C., Schuelke, M. & Seelow, D. MutationTaster evaluates disease-causing potential of sequence alterations. Nat. Methods 7, 575–576 (2010).

    Article  CAS  PubMed  Google Scholar 

  5. Gentry, H.R. et al. Structural and biochemical characterization of CIB1 delineates a new family of EF-hand–containing proteins. J. Biol. Chem. 280, 8407–8415 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Blazejczyk, M. et al. Biochemical characterization and expression analysis of a novel EF-hand Ca2+ binding protein calmyrin2 (Cib2) in brain indicates its function in NMDA receptor mediated Ca2+ signaling. Arch. Biochem. Biophys. 487, 66–78 (2009).

    Article  CAS  PubMed  Google Scholar 

  7. Huang, H., Ishida, H., Yamniuk, A.P. & Vogel, H.J. Solution structures of Ca2+-CIB1 and Mg2+-CIB1 and their interactions with the platelet integrin αIIb cytoplasmic domain. J. Biol. Chem. 286, 17181–17192 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Huang, H. & Vogel, H.J. Structural basis for the activation of platelet integrin αIIbβ3 by calcium- and integrin-binding protein 1. J. Am. Chem. Soc. 134, 3864–3872 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Häger, M. et al. Cib2 binds integrin α7Bβ1D and is reduced in laminin α2 chain–deficient muscular dystrophy. J. Biol. Chem. 283, 24760–24769 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Kasri, N.N. et al. Regulation of InsP3 receptor activity by neuronal Ca2+-binding proteins. EMBO J. 23, 312–321 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Hennigs, J.K. et al. Sweet taste receptor interacting protein CIB1 is a general inhibitor of InsP3-dependent Ca2+ release in vivo. J. Neurochem. 106, 2249–2262 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Mammano, F. et al. ATP-induced Ca2+ release in cochlear outer hair cells: localization of an inositol triphosphate–gated Ca2+ store to the base of the sensory hair bundle. J. Neurosci. 19, 6918–6929 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. White, C., Yang, J., Monteiro, M.J. & Foskett, J.K. CIB1, a ubiquitously expressed Ca2+-binding protein ligand of the InsP3 receptor Ca2+ release channel. J. Biol. Chem. 281, 20825–20833 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Beurg, M., Nam, J.H., Chen, Q. & Fettiplace, R. Calcium balance and mechanotransduction in rat cochlear hair cells. J. Neurophysiol. 104, 18–34 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Reiners, J., Nagel-Wolfrum, K., Jurgens, K., Marker, T. & Wolfrum, U. Molecular basis of human Usher syndrome: deciphering the meshes of the Usher protein network provides insights into the pathomechanisms of the Usher disease. Exp. Eye Res. 83, 97–119 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. van Wijk, E. et al. The DFNB31 gene product whirlin connects to the Usher protein network in the cochlea and retina by direct association with USH2A and VLGR1. Hum. Mol. Genet. 15, 751–765 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Belyantseva, I.A. et al. Myosin-XVa is required for tip localization of whirlin and differential elongation of hair-cell stereocilia. Nat. Cell Biol. 7, 148–156 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Gale, J.E., Marcotti, W., Kennedy, H.J., Kros, C.J. & Richardson, G.P. FM1-43 dye behaves as a permeant blocker of the hair-cell mechanotransducer channel. J. Neurosci. 21, 7013–7025 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Meyers, J.R. et al. Lighting up the senses: FM1-43 loading of sensory cells through nonselective ion channels. J. Neurosci. 23, 4054–4065 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Seiler, C. et al. Myosin VI is required for structural integrity of the apical surface of sensory hair cells in zebrafish. Dev. Biol. 272, 328–338 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Seiler, C. & Nicolson, T. Defective calmodulin-dependent rapid apical endocytosis in zebrafish sensory hair cell mutants. J. Neurobiol. 41, 424–434 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Lumpkin, E.A. & Hudspeth, A.J. Regulation of free Ca2+ concentration in hair-cell stereocilia. J. Neurosci. 18, 6300–6318 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Denk, W., Holt, J.R., Shepherd, G.M. & Corey, D.P. Calcium imaging of single stereocilia in hair cells: localization of transduction channels at both ends of tip links. Neuron 15, 1311–1321 (1995).

    Article  CAS  PubMed  Google Scholar 

  24. Fettiplace, R. & Ricci, A.J. Adaptation in auditory hair cells. Curr. Opin. Neurobiol. 13, 446–451 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Brandt, A., Striessnig, J. & Moser, T. CaV1.3 channels are essential for development and presynaptic activity of cochlear inner hair cells. J. Neurosci. 23, 10832–10840 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Fuchs, P.A., Glowatzki, E. & Moser, T. The afferent synapse of cochlear hair cells. Curr. Opin. Neurobiol. 13, 452–458 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Dulon, D., Zajic, G. & Schacht, J. Increasing intracellular free calcium induces circumferential contractions in isolated cochlear outer hair cells. J. Neurosci. 10, 1388–1397 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dallos, P. et al. Acetylcholine, outer hair cell electromotility, and the cochlear amplifier. J. Neurosci. 17, 2212–2226 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Frolenkov, G.I., Mammano, F., Belyantseva, I.A., Coling, D. & Kachar, B. Two distinct Ca2+-dependent signaling pathways regulate the motor output of cochlear outer hair cells. J. Neurosci. 20, 5940–5948 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Benser, M.E., Marquis, R.E. & Hudspeth, A.J. Rapid, active hair bundle movements in hair cells from the bullfrog's sacculus. J. Neurosci. 16, 5629–5643 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hudspeth, A.J. Hair-bundle mechanics and a model for mechanoelectrical transduction by hair cells. Soc. Gen. Physiol. Ser. 47, 357–370 (1992).

    CAS  PubMed  Google Scholar 

  32. Eatock, R.A., Corey, D.P. & Hudspeth, A.J. Adaptation of mechanoelectrical transduction in hair cells of the bullfrog's sacculus. J. Neurosci. 7, 2821–2836 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ricci, A.J., Wu, Y.C. & Fettiplace, R. The endogenous calcium buffer and the time course of transducer adaptation in auditory hair cells. J. Neurosci. 18, 8261–8277 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wood, J.D., Muchinsky, S.J., Filoteo, A.G., Penniston, J.T. & Tempel, B.L. Low endolymph calcium concentrations in deafwaddler2J mice suggest that PMCA2 contributes to endolymph calcium maintenance. J. Assoc. Res. Otolaryngol. 5, 99–110 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Yamoah, E.N. et al. Plasma membrane Ca2+-ATPase extrudes Ca2+ from hair cell stereocilia. J. Neurosci. 18, 610–624 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Baird, R.A., Steyger, P.S. & Schuff, N.R. Intracellular distributions and putative functions of calcium-binding proteins in the bullfrog vestibular otolith organs. Hear. Res. 103, 85–100 (1997).

    Article  CAS  PubMed  Google Scholar 

  37. Walker, R.G., Hudspeth, A.J. & Gillespie, P.G. Calmodulin and calmodulin-binding proteins in hair bundles. Proc. Natl. Acad. Sci. USA 90, 2807–2811 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hackney, C.M., Mahendrasingam, S., Penn, A. & Fettiplace, R. The concentrations of calcium buffering proteins in mammalian cochlear hair cells. J. Neurosci. 25, 7867–7875 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Dechesne, C.J. et al. Identification and ultrastructural localization of a calretinin-like calcium-binding protein (protein 10) in the guinea pig and rat inner ear. Brain Res. 560, 139–148 (1991).

    Article  CAS  PubMed  Google Scholar 

  40. Yang, D., Thalmann, I., Thalmann, R. & Simmons, D.D. Expression of α and β parvalbumin is differentially regulated in the rat organ of corti during development. J. Neurobiol. 58, 479–492 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Sakaguchi, N., Henzl, M.T., Thalmann, I., Thalmann, R. & Schulte, B.A. Oncomodulin is expressed exclusively by outer hair cells in the organ of Corti. J. Histochem. Cytochem. 46, 29–40 (1998).

    Article  CAS  PubMed  Google Scholar 

  42. Hackney, C.M., Mahendrasingam, S., Jones, E.M. & Fettiplace, R. The distribution of calcium buffering proteins in the turtle cochlea. J. Neurosci. 23, 4577–4589 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Dumont, R.A. et al. Plasma membrane Ca2+-ATPase isoform 2a is the PMCA of hair bundles. J. Neurosci. 21, 5066–5078 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hill, J.K. et al. Splice-site A choice targets plasma-membrane Ca2+-ATPase isoform 2 to hair bundles. J. Neurosci. 26, 6172–6180 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Silverstein, R.S. & Tempel, B.L. Atp2b2, encoding plasma membrane Ca2+-ATPase type 2, (PMCA2) exhibits tissue-specific first exon usage in hair cells, neurons, and mammary glands of mice. Neuroscience 141, 245–257 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Street, V.A., McKee-Johnson, J.W., Fonseca, R.C., Tempel, B.L. & Noben-Trauth, K. Mutations in a plasma membrane Ca2+-ATPase gene cause deafness in deafwaddler mice. Nat. Genet. 19, 390–394 (1998).

    Article  CAS  PubMed  Google Scholar 

  47. Jones, S.M. et al. Stimulus and recording variables and their effects on mammalian vestibular evoked potentials. J. Neurosci. Methods 118, 23–31 (2002).

    Article  PubMed  Google Scholar 

  48. Chintapalli, V.R., Wang, J. & Dow, J.A. Using FlyAtlas to identify better Drosophila melanogaster models of human disease. Nat. Genet. 39, 715–720 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. O'Tousa, J.E. Ca2+ regulation of Drosophila phototransduction. Adv. Exp. Med. Biol. 514, 493–505 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Wang, T. & Montell, C. Phototransduction and retinal degeneration in. Drosophila. Pflugers Arch. 454, 821–847 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Gu, Y., Oberwinkler, J., Postma, M. & Hardie, R.C. Mechanisms of light adaptation in Drosophila photoreceptors. Curr. Biol. 15, 1228–1234 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. Nicolson, T. et al. Genetic analysis of vertebrate sensory hair cell mechanosensation: the zebrafish circler mutants. Neuron 20, 271–283 (1998).

    Article  CAS  PubMed  Google Scholar 

  53. Riazuddin, S. et al. Tricellulin is a tight-junction protein necessary for hearing. Am. J. Hum. Genet. 79, 1040–1051 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Arnold, K., Bordoli, L., Kopp, J. & Schwede, T. The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinformatics 22, 195–201 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Venselaar, H., Te Beek, T.A., Kuipers, R.K., Hekkelman, M.L. & Vriend, G. Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces. BMC Bioinformatics 11, 548 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Belyantseva, I.A. Helios Gene Gun–mediated transfection of the inner ear sensory epithelium. Methods Mol. Biol. 493, 103–123 (2009).

    Article  CAS  PubMed  Google Scholar 

  57. Nasevicius, A. & Ekker, S.C. Effective targeted gene 'knockdown' in zebrafish. Nat. Genet. 26, 216–220 (2000).

    Article  CAS  PubMed  Google Scholar 

  58. Sidi, S., Friedrich, R.W. & Nicolson, T. NompC TRP channel required for vertebrate sensory hair cell mechanotransduction. Science 301, 96–99 (2003).

    Article  CAS  PubMed  Google Scholar 

  59. Dietzl, G. et al. A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila. Nature 448, 151–156 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Lee, Y.S. & Carthew, R.W. Making a better RNAi vector for Drosophila: use of intron spacers. Methods 30, 322–329 (2003).

    Article  CAS  PubMed  Google Scholar 

  61. Wernet, M.F. et al. Homothorax switches function of Drosophila photoreceptors from color to polarized light sensors. Cell 115, 267–279 (2003).

    Article  CAS  PubMed  Google Scholar 

  62. Pichaud, F. & Desplan, C. A new visualization approach for identifying mutations that affect differentiation and organization of the Drosophila ommatidia. Development 128, 815–826 (2001).

    Article  CAS  PubMed  Google Scholar 

  63. Charlton-Perkins, M. et al. Prospero and Pax2 combinatorially control neural cell fate decisions by modulating Ras- and Notch-dependent signaling. Neural Dev. 6, 20 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

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.

Author information

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
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Inna A Belyantseva
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arnaud P J Giese
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kwanghyuk Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Artur A Indzhykulian
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sri Pratima Nandamuri
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rizwan Yousaf
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ghanshyam P Sinha
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sue Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. David Terrell
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Rashmi S Hegde
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Rana A Ali
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Saima Anwar
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Paula B Andrade-Elizondo
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Asli Sirmaci
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Leslie V Parise
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Sulman Basit
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Abdul Wali
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Muhammad Ayub
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Muhammad Ansar
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Wasim Ahmad
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Shaheen N Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Javed Akram
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Mustafa Tekin
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Sheikh Riazuddin
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Tiffany Cook
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Elke K Buschbeck
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Gregory I Frolenkov
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. Suzanne M Leal
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. Thomas B Friedman
    View author publications

    You can also search for this author in PubMed Google Scholar

  31. Zubair M Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding author

Correspondence to Zubair M Ahmed.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–16 and Supplementary Tables 1–7 (PDF 12616 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2426

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing