Alternative titles; symbols
HGNC Approved Gene Symbol: CIB2
Cytogenetic location: 15q25.1 Genomic coordinates (GRCh38) : 15:78,104,606-78,131,535 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q25.1 | Deafness, autosomal recessive 48 | 609439 | Autosomal recessive | 3 |
| Usher syndrome, type IJ | 614869 | Autosomal recessive | 3 |
The CIB2 gene encodes a protein belonging to a family of calcium- and integrin-binding proteins containing 3 or 4 EF-hand domains that change conformation upon binding of calcium and presumably mediate intracellular calcium signaling. CIB2 has conserved roles in calcium homeostasis (summary by Riazuddin et al., 2012).
DNA-dependent protein kinases (DNA-PK) play a role in the repair of double-strand DNA breaks and in the process of V(D)J recombination during lymphoid development. By EST database searching for sequences homologous to the DNA-PK gene KIP/CIB (602293) and 5-prime RACE, Seki et al. (1999) isolated a full-length cDNA, which they designated KIP2, from a human fetal brain cDNA library. KIP2 encodes a deduced 187-amino acid protein with a predicted molecular mass of 22 kD. The KIP2 protein shares 46%, 39%, and 30% sequence identity with the calcium-binding proteins KIP/CIB (602293), calcineurin B (601302), and calmodulin (114180), respectively. Sequence analysis of KIP2 revealed 2 EF-hand motifs and a helix-loop-helix motif involved in coordinating the calcium ion, indicating that KIP2 may also bind calcium. RT-PCR analysis indicated that KIP2 is ubiquitously expressed in various human tissues.
Riazuddin et al. (2012) found that CIB2 was widely expressed in human and adult and embryonic mouse tissues, including in the inner ear and retina. There was a 57-fold enrichment of Cib2 mRNA in mouse cochlear hair cells at postnatal day 7 compared to supporting cells. Cib2 immunoreactivity was first observed at P2 in the organ of Corti and vestibular organs. In adult mouse, Cib2 was observed in the cytoplasm of supporting cells and was concentrated toward the tips of stereocilia of the inner and outer hair cells and vestibular hair cells. Its localization there may reflect involvement in calcium signaling that regulates mechanoelectrical transduction. In the mouse retina, Cib2 was present in inner and outer segments of photoreceptor cells and in the retinal pigmented epithelium. There was also immunoreactivity in the inner and outer plexiform layers and in ganglion cells.
The CIB2 gene contains 6 exons encoding 3 different isoforms (summary by Riazuddin et al., 2012).
Using a radiation hybrid panel and FISH analyses, Seki et al. (1999) localized the KIP2 gene to chromosome 15q24. Since the KIP/CIB gene maps to 15q25.3-q26.1, the authors suggested that KIP2 and CIB are likely 2 isologs derived from an intrachromosomal gene duplication.
In COS-7 cells, Riazuddin et al. (2012) found that expression of wildtype CIB2 caused a 40% decrease in ATP-induced calcium release compared to cells transfected with empty vector, suggesting that CIB2 has an inhibitory effect on calcium responses. CIB2 interacted with and multimerized with whirlin (WHRN; 607928) and with myosin VIIa (MYO7A; 276903), 2 proteins implicated in Usher syndrome (see, e.g., 276900).
Autosomal Recessive Deafness 48
In affected members of 54 Pakistani families with autosomal recessive deafness-48 (DFNB48; 609439), Riazuddin et al. (2012) identified a homozygous mutation in the CIB2 gene (F91S; 605564.0001). Two additional homozygous CIB2 mutations were found in other families with DFNB48 (C99W, 605564.0002 and I123T, 605564.0003). Riazuddin et al. (2012) estimated that CIB2 mutations may account for up to 7.25% of Pakistani families with autosomal recessive deafness. Transfection of the F91S and C99W mutations in COS-7 cells decreased or abolished the ability of CIB2 to decrease ATP-induced calcium release from the cell compared to wildtype, whereas transfection of the I123T mutation increased the ability of CIB2 to decrease calcium release compared to wildtype. These findings suggested that the mutations had an effect on CIB2 calcium-binding or buffering activity. Studies in zebrafish and Drosophila (see ANIMAL MODEL) indicated that Cib2 is important for the function and proper development of hair cells in the ear and photoreceptor cells in the eye. Overall, the results indicated that loss of Cib2 results in defects in calcium regulation.
Usher Syndrome, Type IJ
In affected members of a large consanguineous Turkish family with Usher syndrome type IJ (USH1J; 614869) originally reported by Ahmed et al. (2009) as family PKDF117, Riazuddin et al. (2012) identified a homozygous mutation in the CIB2 gene (E64D; 605564.0004). Transfection of the mutation into COS-7 cells significantly decreased the ability of CIB2 to decrease ATP-induced calcium release from the cell compared to wildtype.
Riazuddin et al. (2012) found that knockdown of Cib2 in zebrafish resulted in a mutant phenotype, including microphthalmia, curled tail, hypopigmentation, and edematous heart. Mutant zebrafish had a marked decrease in the number and function of mechanosensory hair cells, did not respond to acoustic stimuli, and were unable to remain upright while swimming. Knockdown of a Drosophila Cib2-related gene decreased photoresponse amplitude and impaired responses to flicker stimuli at high frequencies. These flies showed photoreceptor degeneration when raised under constant light, suggesting that Cib2 is required for proper phototransduction and prevention of light-dependent retinal degeneration. The phenotypes indicated that loss of Cib2 resulting in defects in calcium regulation can contribute to mechanotransduction defects and defects in photoreceptor maintenance.
In affected members of 54 Pakistani families with autosomal recessive deafness-48 (DFNB48; 609439), Riazuddin et al. (2012) identified a homozygous 272T-C transition in the CIB2 gene, resulting in a phe91-to-ser (F91S) substitution at a highly conserved residue in the first EF-hand binding domain. Haplotype analysis was consistent with a founder effect. The F91S mutation was found in 1 of 1,068 Pakistani control chromosomes, but not in several large exome databases. Transfection of the mutation into COS-7 cells significantly decreased the ability of CIB2 to decrease ATP-induced calcium release from the cell compared to wildtype.
In affected members of 2 Pakistani families with DFNB48 (609439), Riazuddin et al. (2012) identified a homozygous 297C-G transversion in the CIB2 gene, resulting in a cys99-to-trp (C99W) substitution at a highly conserved residue. Haplotype analysis was consistent with a founder effect. The C99W mutation was found in 5 of 1,068 Pakistani control chromosomes, but not in several large exome databases. Transfection of the mutation into COS-7 cells abolished the ability of CIB2 to decrease ATP-induced calcium release from the cell.
In affected members of a Turkish family with DFNB48 (609439), Riazuddin et al. (2012) identified a homozygous 368T-C transition in the CIB2 gene, resulting in an ile123-to-thr (I123T) substitution at a highly conserved residue in the second EF-hand binding domain. The mutation was not found in 724 control chromosomes. Transfection of the mutation into COS-7 cells significantly increased the ability of CIB2 to decrease ATP-induced calcium release from the cell compared to wildtype.
In affected members of a large consanguineous Turkish family with Usher syndrome type IJ (USH1J; 614869) originally reported by Ahmed et al. (2009) as family PKDF117, Riazuddin et al. (2012) identified a homozygous 192G-C transversion in the CIB2 gene, resulting in a glu64-to-asp (E64D) substitution at a highly conserved residue. The mutation was not found in 676 control chromosomes. Transfection of the mutation into COS-7 cells significantly decreased the ability of CIB2 to decrease ATP-induced calcium release from the cell compared to wildtype.
Ahmed, Z. M., Riazuddin, S., Khan, S. N., Friedman, P. L., Riazuddin, S., Friedman, T. B. USH1H, a novel locus for type I Usher syndrome, maps to chromosome 15q22-23. Clin. Genet. 75: 86-91, 2009. [PubMed: 18505454] [Full Text: https://doi.org/10.1111/j.1399-0004.2008.01038.x]
Riazuddin, S., Belyantseva, I. A., Giese, A. P. J., Lee, K., Indzhykulian, A. A., Nandamuri, S. P., Yousaf, R., Sinha, G. P., Lee, S., Terrell, D., Hegde, R. S., Ali, R. A., and 19 others. Alterations of the CIB2 calcium- and integrin-binding protein cause Usher syndrome type 1J and nonsyndromic deafness DFNB48. Nature Genet. 44: 1265-1271, 2012. [PubMed: 23023331] [Full Text: https://doi.org/10.1038/ng.2426]
Seki, N., Hattori, A., Hayashi, A., Kozuma, S., Ohira, M., Hori, T., Saito, T. Structure, expression profile and chromosomal location of an isolog of DNA-PKcs interacting protein (KIP) gene. Biochim. Biophys. Acta 1444: 143-147, 1999. [PubMed: 9931475] [Full Text: https://doi.org/10.1016/s0167-4781(98)00253-x]