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

Patel, Kavisha; Giese, Arnaud P. J.; Grossheim, Jonathan M; Hegde, Rashima S.; Delio, Maria; Samanich, Joy; Riazuddin, Saima; Frolenkov, Gregory I.; Cai, Jinlu; Ahmed, Zubair M.; Morrow, Bernice E.

doi:10.1371/journal.pone.0133082

Cited by 26 publications

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“…The profound deafness observed in CIB2 −/− mice, lacking a functional CIB2 protein for all four Cib2 splice isoforms (Fig A, see also Giese et al , ; Zou et al , ), is reminiscent of the prelingual severe‐to‐profound hearing loss observed in DFNB48‐affected patients (Riazuddin et al , ; Patel et al , ; Seco et al , ; and this study). However, none of the cochlear phenotypes associated with the lack of CIB2 described above were observed in CIB2‐defective vestibular organs.…”

Section: Discussionsupporting

confidence: 67%

“…These expression studies therefore provided no support for a potential link between CIB2 and Usher syndrome. Finally, following on from the initial identification of CIB2 mutations in Pakistani and Turkish families (Riazuddin et al , ), new CIB2 mutations have been found in Dutch, Caribbean Hispanic (Patel et al , ; Seco et al , ) and Iranian and Palestinian Arab (this study, see Fig A–C) families. Of all the nine mutations of CIB2 described to date (including those described here), only the p.Glu64Asp missense variant, described in one Pakistani family, has been reported to cause USH1J (Riazuddin et al , ).…”

Section: Discussionsupporting

confidence: 56%

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CIB2, defective in isolated deafness, is key for auditory hair cell mechanotransduction and survival

et al. 2017

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Defects of CIB2, calcium‐ and integrin‐binding protein 2, have been reported to cause isolated deafness, DFNB48 and Usher syndrome type‐IJ, characterized by congenital profound deafness, balance defects and blindness. We report here two new nonsense mutations (pGln12* and pTyr110*) in CIB2 patients displaying nonsyndromic profound hearing loss, with no evidence of vestibular or retinal dysfunction. Also, the generated CIB2 −/− mice display an early onset profound deafness and have normal balance and retinal functions. In these mice, the mechanoelectrical transduction currents are totally abolished in the auditory hair cells, whilst they remain unchanged in the vestibular hair cells. The hair bundle morphological abnormalities of CIB2 −/− mice, unlike those of mice defective for the other five known USH1 proteins, begin only after birth and lead to regression of the stereocilia and rapid hair‐cell death. This essential role of CIB2 in mechanotransduction and cell survival that, we show, is restricted to the cochlea, probably accounts for the presence in CIB2 −/− mice and CIB2 patients, unlike in Usher syndrome, of isolated hearing loss without balance and vision deficits.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionsupporting

confidence: 56%

CIB2, defective in isolated deafness, is key for auditory hair cell mechanotransduction and survival

et al. 2017

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“…The deletion was on data from other missense variants in CIB2, which do not have this type of impact. [12][13][14][15] It is unclear whether CIB2 p.Cys115 would affect the interaction with TMC1 or TMC2. 15 The p.Val75Met variant has been previously described 17 ( Figure 1F).…”

Section: Discussionmentioning

confidence: 99%

“…Missense variants in CIB2 also do not affect protein localization. [12][13][14][15] There are also important phenotypic differences. Mouse models of USH caused by MYO7A, USH1C, CDH23, PDCH15 and USH1G (the genes responsible for USH1B, USH1C, USH1D, USH1F and USH1G, respectively, in humans) all share a common phenotype: congenital profound deafness and vestibular dysfunction manifested as a visible head-bobbing and circling phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…Two mechanisms have been proposed: a decrease in CIB2 integrin-binding ability or a diminished capacity to properly buffer calcium. [12][13][14] Recent studies in several murine mutants suggest both mechanisms could be at play and might not be mutually exclusive 15,16 . Results from Giese et al suggest that variants in different regions of the CIB2 protein cause distinct effects.…”

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Variants in CIB2 cause DFNB48 and not USH1J

et al. 2018

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The genetic, mutational and phenotypic spectrum of deafness-causing genes shows great diversity and pleiotropy. The best examples are the group of genes, which when mutated can either cause non-syndromic hearing loss (NSHL) or the most common dual sensory impairment, Usher syndrome (USH). Variants in the CIB2 gene have been previously reported to cause hearing loss at the DFNB48 locus and deaf-blindness at the USH1J locus. In this study, we characterize the phenotypic spectrum in a multiethnic cohort with autosomal recessive non-syndromic hearing loss (ARNSHL) due to variants in the CIB2 gene. Of the 6 families we ascertained, 3 segregated novel loss-of-function (LOF) variants, 2 families segregated missense variants (1 novel) and 1 family segregated a previously reported pathogenic variant in trans with a frameshift variant. This report is the first to show that biallelic LOF variants in CIB2 cause ARNSHL and not USH. In the era of precision medicine, providing the correct diagnosis (NSHL vs USH) is essential for patient care as it impacts potential intervention and prevention options for patients. Here, we provide evidence disqualifying CIB2 as an USH-causing gene.

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Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss

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Faridi

et al. 2018

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Consanguineous Pakistani pedigrees segregating deafness have contributed decisively to the discovery of 31 of the 68 genes associated with nonsyndromic autosomal recessive hearing loss (HL) worldwide. In this study, we utilized genome-wide genotyping, Sanger and exome sequencing to identify 163 DNA variants in 41 previously reported HL genes segregating in 321 Pakistani families. Of these, 71 (43.6%) variants identified in 29 genes are novel. As expected from genetic studies of disorders segregating in consanguineous families, the majority of affected individuals (94.4%) are homozygous for HL-associated variants, with the other variants being compound heterozygotes. The five most common HL genes in the Pakistani population are SLC26A4, MYO7A, GJB2, CIB2 and HGF, respectively. Our study provides a profile of the genetic etiology of HL in Pakistani families, which will allow for the development of more efficient genetic diagnostic tools, aid in accurate genetic counseling and guide application of future gene-based therapies. These findings are also valuable in interpreting pathogenicity of variants that are potentially associated with HL in individuals of all ancestries. The Pakistani population, and its infrastructure for studying human genetics, will continue to be valuable to gene discovery for HL and other inherited disorders.

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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

Cited by 26 publications

References 43 publications

CIB2, defective in isolated deafness, is key for auditory hair cell mechanotransduction and survival

CIB2, defective in isolated deafness, is key for auditory hair cell mechanotransduction and survival

Variants in CIB2 cause DFNB48 and not USH1J

Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss

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