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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

Mutation in penultimate amino acid of CIB2.(A) Chromatogram from Sanger sequencing showing that both affected children have a homozygous c.556C>T (p.Arg186Trp) mutation and the parents are heterozygous carriers. The chromatogram of the proband is shown and the sibling has an identical chromatogram (not shown). (B) The mutation affects the arginine residue at amino acid position 186 of CIB2, which is the penultimate amino acid of the protein. The genomic position of the nucleotide variant is on chromosome 15, position 78,397,660 on human February 2009, GRCh37/hg19 assembly. (C) The arginine residue at amino acid position 186 is conserved across a wide variety of species. Identical residues are highlighted in gray color.
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pone.0133082.g002: Mutation in penultimate amino acid of CIB2.(A) Chromatogram from Sanger sequencing showing that both affected children have a homozygous c.556C>T (p.Arg186Trp) mutation and the parents are heterozygous carriers. The chromatogram of the proband is shown and the sibling has an identical chromatogram (not shown). (B) The mutation affects the arginine residue at amino acid position 186 of CIB2, which is the penultimate amino acid of the protein. The genomic position of the nucleotide variant is on chromosome 15, position 78,397,660 on human February 2009, GRCh37/hg19 assembly. (C) The arginine residue at amino acid position 186 is conserved across a wide variety of species. Identical residues are highlighted in gray color.

Mentions: Through this initial search, we identified a homozygous mutation in CIB2 (c.556C>T; p.(Arg186Trp)) in both affected siblings, whereas the healthy parents are unaffected carriers (Fig 2). The c.556C>T (p.Arg186Trp) mutation is located in exon 6 of CIB2, which encodes the carboxy-terminal end of the resulting polypeptide. The mutation in the female proband found by WES was validated by Sanger sequence analysis (Fig 2A). This nucleotide change was not observed in the normal population (1000 Genomes Project; NHLBI ESP6500). We performed a mutation specific restriction enzyme digest (Fig 3) in 94 ethnically matched (Hispanic) and a 100 African American unrelated healthy individuals and did not identify the mutation in any of the subjects, suggesting this mutation is truly rare in both populations (data not shown). This nucleotide change has been observed as a rare heterozygous variant in an African American control samples and was absent in a further 8586 European controls samples studied, as part of the NHLBI Exome Sequencing Project (ESP; S1 Table).


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)

Mutation in penultimate amino acid of CIB2.(A) Chromatogram from Sanger sequencing showing that both affected children have a homozygous c.556C>T (p.Arg186Trp) mutation and the parents are heterozygous carriers. The chromatogram of the proband is shown and the sibling has an identical chromatogram (not shown). (B) The mutation affects the arginine residue at amino acid position 186 of CIB2, which is the penultimate amino acid of the protein. The genomic position of the nucleotide variant is on chromosome 15, position 78,397,660 on human February 2009, GRCh37/hg19 assembly. (C) The arginine residue at amino acid position 186 is conserved across a wide variety of species. Identical residues are highlighted in gray color.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0133082.g002: Mutation in penultimate amino acid of CIB2.(A) Chromatogram from Sanger sequencing showing that both affected children have a homozygous c.556C>T (p.Arg186Trp) mutation and the parents are heterozygous carriers. The chromatogram of the proband is shown and the sibling has an identical chromatogram (not shown). (B) The mutation affects the arginine residue at amino acid position 186 of CIB2, which is the penultimate amino acid of the protein. The genomic position of the nucleotide variant is on chromosome 15, position 78,397,660 on human February 2009, GRCh37/hg19 assembly. (C) The arginine residue at amino acid position 186 is conserved across a wide variety of species. Identical residues are highlighted in gray color.
Mentions: Through this initial search, we identified a homozygous mutation in CIB2 (c.556C>T; p.(Arg186Trp)) in both affected siblings, whereas the healthy parents are unaffected carriers (Fig 2). The c.556C>T (p.Arg186Trp) mutation is located in exon 6 of CIB2, which encodes the carboxy-terminal end of the resulting polypeptide. The mutation in the female proband found by WES was validated by Sanger sequence analysis (Fig 2A). This nucleotide change was not observed in the normal population (1000 Genomes Project; NHLBI ESP6500). We performed a mutation specific restriction enzyme digest (Fig 3) in 94 ethnically matched (Hispanic) and a 100 African American unrelated healthy individuals and did not identify the mutation in any of the subjects, suggesting this mutation is truly rare in both populations (data not shown). This nucleotide change has been observed as a rare heterozygous variant in an African American control samples and was absent in a further 8586 European controls samples studied, as part of the NHLBI Exome Sequencing Project (ESP; S1 Table).

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