Alternative titles; symbols
HGNC Approved Gene Symbol: CYFIP1
Cytogenetic location: 15q11.2 Genomic coordinates (GRCh38) : 15:22,867,052-22,980,898 (from NCBI)
By sequencing clones obtained from an immature myeloid cell line (KG-1) cDNA library, Nomura et al. (1994) cloned CYFIP1, which they designated KIAA0068. The deduced protein contains 1,271 amino acids. Northern blot analysis detected CYFIP1 expression in all human tissues and cell lines examined. Highest expression was in lung, kidney, spleen, prostate, and ovary, as well as in HeLa cells and KG-1 cells.
To identify novel proteins that interact with the fragile X mental retardation protein (FMRP), encoded by the FMR1 gene (309550), Schenck et al. (2001) used yeast 2-hybrid screening with the FMRP N terminus as bait. They identified 2 proteins as FMRP interactors, CYFIP1 and CYFIP2 (606323). CYFIP1 contains 1,253 amino acids and shares 88% sequence identity with CYFIP2. CYFIP1 and CYFIP2 are members of a highly conserved protein family and share approximately 99% sequence identity with their mouse orthologs.
By genomic sequence analysis to identify novel genes adjacent to the imprinted domain in the Prader-Willi syndrome (PWS; 176270)/Angelman (AS; 105830) syndrome deletion region of chromosome 15, Chai et al. (2003) identified CYFIP1. Northern blot analysis detected a 4.4-kb transcript in all human and mouse tissues examined, with highest expression in placenta.
Schenck et al. (2001) found that CYFIP1 interacts exclusively with FMRP, whereas CYFIP2 also interacts with the FMRP-related proteins FXR1P (600819) and FXR2P (605339). The interaction of FMRP and CYFIP involves the domain of FMRP that also mediates homo- and heteromerization, suggesting a competition between interaction among the FXR proteins and interaction with CYFIP. Schenck et al. (2001) determined that CYFIP1 and CYFIP2 are distributed in an identical pattern in the cytoplasm, showing colocalization with FMRP and ribosomes. CYFIP1 has been shown to interact with the small GTPase RAC1 (602048), which is implicated in development and maintenance of neuronal structures (Kobayashi et al., 1998). Consistent with FMRP and RAC1 localization in dendritic fine structures, CYFIP1/2 are present in synaptosomal extracts.
RAC1 stimulates actin remodeling at the cell periphery, leading to lamellipodia formation. Steffen et al. (2004) found that Sra1 and Nap1 (NCKAP1; 604891) interacted with Wave2 (WASF2; 605875) and Abi1 (SSH3BP1; 603050) in resting mouse melanoma cells or following Rac1 activation. Microinjection of constitutively active RAC1 resulted in translocation of Sra1, Nap1, Wave2, and Abi1 to the tips of membrane protrusions. Moreover, removal of SRA1 or NAP1 by RNA interference in human or mouse cells abrogated formation of RAC1-dependent lamellipodia. Microinjection of active RAC1 failed to restore lamellipodia protrusion in cells lacking either SRA1 or NAP1. Steffen et al. (2004) concluded that SRA1 and NAP1 are essential components of a WAVE2- and ABI1-containing complex linking RAC1 to site-directed actin assembly.
Chai et al. (2003) determined that the CYFIP1 gene contains 31 exons and spans 111.4 kb. The 5-prime end is associated with a strong CpG island. The mouse Cyfip1 gene has a similar 31-exon structure.
By analysis of a panel of human-rodent hybrid cell lines, Nomura et al. (1994) mapped the CYFIP1 gene to chromosome 15.
By genomic sequence analysis, Chai et al. (2003) mapped the CYFIP1 gene to chromosome 15q11.2, within a region deleted in some cases of PWS and AS. CYFIP1 lies within a gene cluster distal to breakpoint hotspot 1 (BP1) and proximal to BP2. The order of genes within this cluster is cen-NIPA1 (608145)-NIPA2 (608146)-CYFIP1-GCP5 (608147)-BP2-tel. Chai et al. (2003) mapped the mouse Cyfip1 gene to a region of chromosome 7C that contains the same gene cluster and shows homology of synteny to human chromosome 15q11-q13.
Deletions associated with AS and PWS are either class I, with the deletion extending from BP1 (15q11.2) to BP3 (15q13), or class II, with a more telomeric deletion extending from BP2 (15q11.2) to BP3. Chai et al. (2003) determined that a BAC clone containing exons 7 through 31 of the CYFIP1 gene, which is located between BP1 and BP2, could be used as probe in FISH to distinguish between class I and class II deletions in a panel of cell lines from patients with AS deletions.
By replication-timing studies, Chai et al. (2003) determined that replication of the mouse genomic region spanning Nipa1-Nipa2-Cyfip1 showed a pattern of asynchrony, but the asynchrony was not due to parent-of-origin influences. PCR of mouse brain cDNA from transgenic PWS and AS mouse models indicated that the Nipa1, Nipa2, Cyfip1, and Gcp5 genes are nonimprinted. RT-PCR detected expression of the human NIPA1, NIPA2, CYFIP1, and GCP5 genes in lymphocytes from a normal individual and from PWS and AS imprinting mutation patients. CYFIP1 was expressed from both the maternal and paternal chromosome 15 in somatic cell hybrids, further indicating that these 4 genes are nonimprinted.
Chai, J.-H., Locke, D. P., Greally, J. M., Knoll, J. H. M., Ohta, T., Dunai, J., Yavor, A., Eichler, E. E., Nicholls, R. D. Identification of four highly conserved genes between breakpoint hotspots BP1 and BP2 of the Prader-Willi/Angelman syndromes deletion region that have undergone evolutionary transposition mediated by flanking duplicons. Am. J. Hum. Genet. 73: 898-925, 2003. [PubMed: 14508708] [Full Text: https://doi.org/10.1086/378816]
Kobayashi, K., Kuroda, S., Fukata, M., Nakamura, T., Nagase, T., Nomura, N., Matsuura, Y., Yoshida-Kubomura, N., Iwamatsu, A., Kaibuchi, K. p140Sra-1 (specifically Rac1-associated protein) is a novel specific target for Rac1 small GTPase. J. Biol. Chem. 273: 291-295, 1998. [PubMed: 9417078] [Full Text: https://doi.org/10.1074/jbc.273.1.291]
Nomura, N., Nagase, T., Miyajima, N., Sazuka, T., Tanaka, A., Sato, S., Seki, N., Kawarabayasi, Y., Ishikawa, K., Tabata, S. Prediction of the coding sequences of unidentified human genes. II. The coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis of cDNA clones from human cell line KG-1. DNA Res. 1: 223-229, 1994. [PubMed: 7584044] [Full Text: https://doi.org/10.1093/dnares/1.5.223]
Schenck, A., Bardoni, B., Moro, A., Bagni, C., Mandel, J. L. A highly conserved protein family interacting with the fragile X mental retardation protein (FMRP) and displaying selective interactions with FMRP-related proteins FXR1P and FXR2P. Proc. Nat. Acad. Sci. 98: 8844-8849, 2001. [PubMed: 11438699] [Full Text: https://doi.org/10.1073/pnas.151231598]
Steffen, A., Rottner, K., Ehinger, J., Innocenti, M., Scita, G., Wehland, J., Stradal, T. E. B. Sra-1 and Nap1 link Rac to actin assembly driving lamellipodia formation. EMBO J. 23: 749-759, 2004. [PubMed: 14765121] [Full Text: https://doi.org/10.1038/sj.emboj.7600084]