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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

Pedigree and audiogram of JS6 proband.(A) Pedigree of family JS6 (arrow to proband). The filled symbols represent affected individuals. (B) Audiogram from the female proband, JS6.001 indicating hearing loss ranging from severe to profound. The symbols ‘o’ and ‘x’ denote air conduction pure-tone thresholds, and the ‘A’ symbol denotes bone conduction thresholds. Downward arrow denotes no response on the audiogram.
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pone.0133082.g001: Pedigree and audiogram of JS6 proband.(A) Pedigree of family JS6 (arrow to proband). The filled symbols represent affected individuals. (B) Audiogram from the female proband, JS6.001 indicating hearing loss ranging from severe to profound. The symbols ‘o’ and ‘x’ denote air conduction pure-tone thresholds, and the ‘A’ symbol denotes bone conduction thresholds. Downward arrow denotes no response on the audiogram.

Mentions: We identified a Caribbean Hispanic family in which both affected children have bilateral profound hearing loss diagnosed within the first year of life (Fig 1A). Additional family history was obtained through a medical interview at the time of recruitment. The parents were found to have normal hearing and did not report any medical complication or drug exposure during pregnancy. No evidence for other syndromic features such as Usher syndrome was present. The proband had a normal ocular exam (Ocular exam: VA: 20/25 left, 20/20 right; EOM full. External: OK; Anterior segment: L/L flat on; FUNDUS: = 0.75–1.00 x 180; +2.50–1.50 x 180). There was no evidence for congenital heart disease, respiratory problems, urinary tract abnormalities, thereby ruling out the possibility of CHARGE syndrome. Assessment of auditory brainstem responses (ABR) at 7 months revealed profound impairment with a threshold greater than 90 dB at 250 Hz and greater than 110 dB for all other frequencies tested (Fig 1B). The acoustic reflexes were also absent in both ears. The proband’s brother had bilateral hearing loss (Fig 1A), but there is no other family history of hearing loss. Therefore, based on this information we tentatively concluded that hearing loss in both children is non-syndromic with a possible underlying genetic cause. Mutations in the GJB2 gene had previously been excluded as part of routine clinical management.


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)

Pedigree and audiogram of JS6 proband.(A) Pedigree of family JS6 (arrow to proband). The filled symbols represent affected individuals. (B) Audiogram from the female proband, JS6.001 indicating hearing loss ranging from severe to profound. The symbols ‘o’ and ‘x’ denote air conduction pure-tone thresholds, and the ‘A’ symbol denotes bone conduction thresholds. Downward arrow denotes no response on the audiogram.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0133082.g001: Pedigree and audiogram of JS6 proband.(A) Pedigree of family JS6 (arrow to proband). The filled symbols represent affected individuals. (B) Audiogram from the female proband, JS6.001 indicating hearing loss ranging from severe to profound. The symbols ‘o’ and ‘x’ denote air conduction pure-tone thresholds, and the ‘A’ symbol denotes bone conduction thresholds. Downward arrow denotes no response on the audiogram.
Mentions: We identified a Caribbean Hispanic family in which both affected children have bilateral profound hearing loss diagnosed within the first year of life (Fig 1A). Additional family history was obtained through a medical interview at the time of recruitment. The parents were found to have normal hearing and did not report any medical complication or drug exposure during pregnancy. No evidence for other syndromic features such as Usher syndrome was present. The proband had a normal ocular exam (Ocular exam: VA: 20/25 left, 20/20 right; EOM full. External: OK; Anterior segment: L/L flat on; FUNDUS: = 0.75–1.00 x 180; +2.50–1.50 x 180). There was no evidence for congenital heart disease, respiratory problems, urinary tract abnormalities, thereby ruling out the possibility of CHARGE syndrome. Assessment of auditory brainstem responses (ABR) at 7 months revealed profound impairment with a threshold greater than 90 dB at 250 Hz and greater than 110 dB for all other frequencies tested (Fig 1B). The acoustic reflexes were also absent in both ears. The proband’s brother had bilateral hearing loss (Fig 1A), but there is no other family history of hearing loss. Therefore, based on this information we tentatively concluded that hearing loss in both children is non-syndromic with a possible underlying genetic cause. Mutations in the GJB2 gene had previously been excluded as part of routine clinical management.

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