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A Novel C-Terminal CIB2 (Calcium and Integrin Binding Protein 2) Mutation Associated with Non-Syndromic Hearing Loss in a Hispanic Family.

Patel K, Giese AP, Grossheim JM, Hegde RS, Hegde RS, Delio M, Samanich J, Riazuddin S, Frolenkov GI, Cai J, Ahmed ZM, Morrow BE - PLoS ONE (2015)

Bottom Line: The carboxy-termini of CIB proteins are associated with calcium binding and intracellular signaling.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, New York, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

The p.Arg186Trp mutation does not affect the targeting of CIB2 to the stereocilia tips of vestibular system hair cells.Gene gun transfection of P3 vestibular system with a CIB2WT-GFP expression vector shows targeting of CIB2 to the cell body, the cuticular plate (Pseudocolor, *) and also along the length of stereocilia of hair cells (top set of panels). As previously shown, CIB2 also accumulates to the stereocilia tips (Pseudocolor, arrows). The p.Arg186Trp mutation does not affect the localization of CIB2 in the cuticular plate or to the tip of stereocilia (pseudocolor, *, arrows) as shown in the bottom set of panels. Scale bars, 5μm.
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pone.0133082.g004: The p.Arg186Trp mutation does not affect the targeting of CIB2 to the stereocilia tips of vestibular system hair cells.Gene gun transfection of P3 vestibular system with a CIB2WT-GFP expression vector shows targeting of CIB2 to the cell body, the cuticular plate (Pseudocolor, *) and also along the length of stereocilia of hair cells (top set of panels). As previously shown, CIB2 also accumulates to the stereocilia tips (Pseudocolor, arrows). The p.Arg186Trp mutation does not affect the localization of CIB2 in the cuticular plate or to the tip of stereocilia (pseudocolor, *, arrows) as shown in the bottom set of panels. Scale bars, 5μm.

Mentions: CIB2 is localized to the stereocilia of cochlear and vestibular system hair cells, primarily at the tip of stereocilia of the shortest rows in hair cells, where the mechanotransduction channels are localized [30]. To investigate the effect of p.Arg186Trp mutation on CIB2 targeting to the tip of stereocilia, we overexpressed GFP tagged CIB2R186W protein in postnatal vestibular system explants, using a Helios gene gun mediated transfection system. The targeting of CIB2R186W-GFP was comparable to CIB2WT-GFP (Fig 4). These results suggest that in explant cultures, the p.Arg186Trp alleles do not affect the targeting of CIB2 to the tip of stereocilia.


A Novel C-Terminal CIB2 (Calcium and Integrin Binding Protein 2) Mutation Associated with Non-Syndromic Hearing Loss in a Hispanic Family.

Patel K, Giese AP, Grossheim JM, Hegde RS, Hegde RS, Delio M, Samanich J, Riazuddin S, Frolenkov GI, Cai J, Ahmed ZM, Morrow BE - PLoS ONE (2015)

The p.Arg186Trp mutation does not affect the targeting of CIB2 to the stereocilia tips of vestibular system hair cells.Gene gun transfection of P3 vestibular system with a CIB2WT-GFP expression vector shows targeting of CIB2 to the cell body, the cuticular plate (Pseudocolor, *) and also along the length of stereocilia of hair cells (top set of panels). As previously shown, CIB2 also accumulates to the stereocilia tips (Pseudocolor, arrows). The p.Arg186Trp mutation does not affect the localization of CIB2 in the cuticular plate or to the tip of stereocilia (pseudocolor, *, arrows) as shown in the bottom set of panels. Scale bars, 5μm.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4591343&req=5

pone.0133082.g004: The p.Arg186Trp mutation does not affect the targeting of CIB2 to the stereocilia tips of vestibular system hair cells.Gene gun transfection of P3 vestibular system with a CIB2WT-GFP expression vector shows targeting of CIB2 to the cell body, the cuticular plate (Pseudocolor, *) and also along the length of stereocilia of hair cells (top set of panels). As previously shown, CIB2 also accumulates to the stereocilia tips (Pseudocolor, arrows). The p.Arg186Trp mutation does not affect the localization of CIB2 in the cuticular plate or to the tip of stereocilia (pseudocolor, *, arrows) as shown in the bottom set of panels. Scale bars, 5μm.
Mentions: CIB2 is localized to the stereocilia of cochlear and vestibular system hair cells, primarily at the tip of stereocilia of the shortest rows in hair cells, where the mechanotransduction channels are localized [30]. To investigate the effect of p.Arg186Trp mutation on CIB2 targeting to the tip of stereocilia, we overexpressed GFP tagged CIB2R186W protein in postnatal vestibular system explants, using a Helios gene gun mediated transfection system. The targeting of CIB2R186W-GFP was comparable to CIB2WT-GFP (Fig 4). These results suggest that in explant cultures, the p.Arg186Trp alleles do not affect the targeting of CIB2 to the tip of stereocilia.

Bottom Line: The carboxy-termini of CIB proteins are associated with calcium binding and intracellular signaling.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, New York, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus