Alternative titles; symbols
HGNC Approved Gene Symbol: CLIP2
Cytogenetic location: 7q11.23 Genomic coordinates (GRCh38) : 7:74,289,407-74,405,935 (from NCBI)
Williams-Beuren syndrome (WBS; 194050) is a multisystem developmental disorder caused by the deletion of contiguous genes at 7q11.23. Osborne et al. (1996) characterized a 500-kb region in 7q11.23 that was deleted in a collection of 30 WBS patients (see 603431). By genomic sequencing of this region, they identified the novel transcription unit WSCR4. The WSCR4 gene has at least 7 exons and encodes a protein that contains a motif sharing 73% sequence identity with a microtubule-binding motif in the N-terminal domain of restin (RSN; 179838). Osborne et al. (1996) were unable to detect WSCR4 transcripts in a variety of human tissues using both Northern blot analysis and RT-PCR.
Cytoplasmic linker proteins have been proposed to mediate the interaction between specific membranous organelles and microtubules. Hoogenraad et al. (1998) isolated and characterized overlapping murine and human cosmids respectively containing the complete mouse Cyln2 gene, which encodes cytoplasmic linker protein-115 (Clip-115), and the partial human CYLN2 gene. Based on nucleotide sequence comparisons and hybridization data, they concluded that the human CYLN2 gene includes the incomplete WBSCR4 and WBSCR3 transcription units identified by Osborne et al. (1996). Hoogenraad et al. (1998) found that the human CYLN2 gene spans at least 140 kb of DNA. The deduced partial human CYLN2 protein contains an N-terminal globular region with 2 microtubule-binding domains, followed by a potential alpha-helical coiled-coils region. Northern blot analysis with a rat Cyln2 cDNA probe detected a 5.5-kb CYLN2 message in human adult brain.
By fluorescence in situ hybridization, Hoogenraad et al. (1998) mapped the human and mouse CYLN2 genes to 7q11.23 and the telomeric end of chromosome 5, respectively, regions that show homology of synteny.
Vandeweyer et al. (2012) reported 2 healthy adult sibs with a heterozygous 83-kb deletion involving only the CLIP2 gene. The individuals were ascertained during a study involving a relative with global developmental delay due to another cause. Detailed physical and neurocognitive testing of the sibs with the CLIP2 deletion did not reveal any abnormalities in either individual. The findings suggested that haploinsufficiency for CLIP2 is not critical for the cognitive profile of WBS, which is in contrast to earlier studies that had implicated CLIP2 in some clinical manifestations of the disorder (see, e.g., Tassabehji et al., 2005, Dai et al., 2009; Ferrero et al., 2010).
Using a gene targeting approach, Hoogenraad et al. (2002) provided evidence that mice with haploinsufficiency for Cyln2 have features reminiscent of WBS, including mild growth deficiency, brain abnormalities, hippocampal dysfunction, and particular deficits in motor coordination. Absence of CLIP115 also leads to increased levels of RSN, a closely related cytoplasmic linker protein, and dynactin (DCTN1; 601143) at the tips of growing microtubules. This protein redistribution may affect dynein motor regulation and, together with the loss of CLIP115-specific functions, underlie neurologic alterations in WBS.
Dai, L., Bellugi, U., Chen, X.-N., Pulst-Korenberg, A. M., Jarvinen-Pasley, A., Tirosh-Wagner, T., Eis, P. S., Graham, J., Mills, D., Searcy, Y., Korenberg, J. R. Is it Williams syndrome? GTF2IRD1 implicated in visual-spatial construction and GTF2I in sociability revealed by high resolution arrays. Am. J. Med. Genet. 149A: 302-314, 2009. [PubMed: 19205026] [Full Text: https://doi.org/10.1002/ajmg.a.32652]
Ferrero, G. B., Howald, C., Micale, L, Biamino, E., Augello, B., Fusco, C., Turturo, M. G., Forzano, S., Reymond, A., Merla, G. An atypical 7q11.23 deletion in a normal IQ Williams-Beuren syndrome patient. Europ. J. Hum. Genet. 18: 33-38, 2010. [PubMed: 19568270] [Full Text: https://doi.org/10.1038/ejhg.2009.108]
Hoogenraad, C. C., Eussen, B. H. J., Langeveld, A., van Haperen, R., Winterberg, S., Wouters, C. H., Grosveld, F., De Zeeuw, C. I., Galjart, N. The murine CYLN2 gene: genomic organization, chromosome localization, and comparison to the human gene that is located within the 7q11.23 Williams syndrome critical region. Genomics 53: 348-358, 1998. [PubMed: 9799601] [Full Text: https://doi.org/10.1006/geno.1998.5529]
Hoogenraad, C. C., Koekkoek, B., Akhmanova, A., Krugers, H., Dortland, B., Miedema, M., van Alphen, A., Kistler, W. M., Jaegle, M., Koutsourakis, M., Van Camp, N., Verhoye, M., van der Linden, A., Kaverina, I., Grosveld, F., De Zeeuw, C. I., Galjart, N. Targeted mutation of Cyln2 in the Williams syndrome critical region links CLIP-115 haploinsufficiency to neurodevelopmental abnormalities in mice. Nature Genet. 32: 116-127, 2002. Note: Erratum: Nature Genet. 32: 331 only, 2002. [PubMed: 12195424] [Full Text: https://doi.org/10.1038/ng954]
Osborne, L. R., Martindale, D., Scherer, S. W., Shi, X.-M., Huizenga, J., Heng, H. H. Q., Costa, T., Pober, B., Lew, L., Brinkman, J., Rommens, J., Koop, B., Tsui, L.-C. Identification of genes from a 500-kb region at 7q11.23 that is commonly deleted in Williams syndrome patients. Genomics 36: 328-336, 1996. [PubMed: 8812460] [Full Text: https://doi.org/10.1006/geno.1996.0469]
Tassabehji, M., Hammond, P., Karmiloff-Smith, A., Thompson, P., Thorgeirsson, S. S., Durkin, M. E., Popescu, N. C., Hutton, T., Metcalfe, K., Rucka, A., Stewart, H., Read, A. P., Maconochie, M., Donnai, D. GTF2IRD1 in craniofacial development of humans and mice. Science 310: 1184-1187, 2005. [PubMed: 16293761] [Full Text: https://doi.org/10.1126/science.1116142]
Vandeweyer, G., Van der Aa, N., Reyniers, E., Kooy, R. F. The contribution of CLIP2 haploinsufficiency to the clinical manifestations of the Williams-Beuren syndrome. Am. J. Hum. Genet. 90: 1071-1078, 2012. [PubMed: 22608712] [Full Text: https://doi.org/10.1016/j.ajhg.2012.04.020]