Alternative titles; symbols
HGNC Approved Gene Symbol: CLIP1
Cytogenetic location: 12q24.31 Genomic coordinates (GRCh38) : 12:122,271,469-122,422,956 (from NCBI)
CLIP1 encodes a member of the microtubule (MT) plus-end tracking protein family. It has an important role in spermatogenesis as well as in neuronal development (summary by Larti et al., 2015).
Binding of endocytic carrier vesicles to microtubules depends on the microtubule-binding protein CLIP170 in vitro. In vivo, CLIP170 colocalizes with a subset of transferrin receptor-positive endocytic structures and, more extensively, with endosomal tubules induced by brefeldin A. Pierre et al. (1992) cloned a cDNA for CLIP70 and found that the predicted protein contains 1,392 amino acids. The predicted nonhelical C- and N-terminal domains of the homodimeric protein are connected by a long coiled-coil domain. Pierre et al. (1992) identified a novel motif present in a tandem repeat in the N-terminal domain of CLIP170 that is involved in binding to microtubules. This motif is also found in the Drosophila Glued and yeast BIK1 proteins. These features, together with its very elongated structure, suggested that CLIP170 belongs to a novel class of proteins, designated cytoplasmic linker proteins (CLIPs), that mediate interactions of organelles with microtubules.
Restin, initially thought to be an intermediate filament-associated protein, is in fact associated with microtubules, as shown by immunofluorescence microscopy (Pierre et al., 1994). Its expression is limited to Reed-Sternberg cells, characteristic of Hodgkin disease, and in vitro cultivated peripheral blood monocytes (Bilbe et al., 1992; Delabie et al., 1992). The protein was named restin by Bilbe et al. (1992) because of its specific expression in the Reed-Sternberg cell. Bilbe et al. (1992) suggested that its overexpression may be a contributing factor in the progression of Hodgkin disease. Delabie et al. (1992) found that restin was not detectable in normal tissues, a range of B- and T-cell non-Hodgkin lymphomas, and nonlymphoid tumors. Restin was present in Reed-Sternberg cells and variants thereof in Hodgkin disease, with the exception of the lymphocyte-predominant, paragranuloma subtype. Irsch et al. (1998) described the isolation of viable mononucleated Hodgkin and Reed-Sternberg and bi- or oligonucleated Reed-Sternberg cells from Hodgkin disease tissues.
CLIP170 and restin are identical except for a 35-amino acid insert in restin that is absent in CLIP170. Griparic and Keller (1998) identified 2 variants of CLIP170: CLIP170(11), which contains an 11-amino acid insert instead of the 35-amino acid restin insert, and CLIP170(11+35), which contains both the 11-amino acid insert and the 35-amino acid restin insert. Both novel isoforms were found to be preferentially expressed in muscle tissue.
Perez et al. (1999) found that CLIP170 binds in stretches along a subset of microtubule ends. These stretches appeared to move with the growing tips of microtubules at 0.15 to 0.4 micro m/s, comparable to microtubule elongation in vivo. Analysis of speckles along dynamic CLIP170 stretches suggested that CLIP170 treadmills on growing microtubule ends rather than being continuously transported toward these ends. Drugs affecting microtubule dynamics rapidly inhibited movement of CLIP170 dashes. Perez et al. (1999) proposed that CLIP170 highlights growing microtubule ends by specifically recognizing the structure of a segment of newly polymerized tubulin.
Fukata et al. (2002) found that IQGAP1 (603379), an effector of RAC1 (602048) and CDC42 (116952), interacts with CLIP170. In Vero fibroblasts, IQGAP1 localized at the polarized leading edge. Expression of a C-terminal fragment of IQGAP1 that included the CLIP170-binding region delocalized GFP-CLIP170 from the tips of microtubules and altered the microtubule array. The authors found that activated RAC1/CDC42, IQGAP1, and CLIP170 form a tripartite complex. Furthermore, expression of an IQGAP1 mutant defective in RAC1/CDC42 binding induced multiple leading edges. These results indicated that RAC1/CDC42 marks special cortical spots where the IQGAP1 and CLIP170 complex is targeted, leading to a polarized microtubule array and cell polarization.
By a combination of chromosomal R-banding and fluorescence in situ hybridization with 2 fluorescent dyes, Hilliker et al. (1994) simultaneously detected the hybridized DNA sequence and chromosomal R-banding. By this technique, they assigned the RSN gene to 12q24.31-q24.33.
See 179837.0001 for discussion of a possible association between an intellectual disability syndrome and variation in the CLIP1 gene.
This variant is classified as a variant of unknown significance because its contribution to an intellectual disability syndrome has not been confirmed.
In affected members of a consanguineous Iranian family with moderate intellectual disability, seizures, strabismus, complete spermatogenic hypoplasia in 1 male, and focal leukodystrophy in the brain MRI of 1 female, Larti et al. (2015) identified a homozygous c.3028C-T transition (c.3028C-T, NM_002956.2) in the CLIP1 gene, resulting in a gln1010-to-ter (Q1010X) substitution, that segregated with the disorder in the family. RT-PCR and Western blot analyses showed the absence of CLIP1 transcript and protein in lymphoblastoid cells derived from affected patients. Immunofluorescence analyses showed MT plus-end staining in fibroblasts containing the wildtype, but not the mutant, CLIP1 protein.
Note: The article by Larti et al. (2015) states that the authors identified the c.3028C-T CLIP1 variant along with other 'excluded' variants listed in their Supplementary Table 1 (ST1) by high-throughput sequencing of the genomic DNA sample of 1 affected family member; however, whereas ST1 lists 39 variants, the Supplementary Information document of the article states that 'for this family we finally reached to a list of 62 variants, provided in supplementary table, ST1.'
Bilbe, G., Delabie, J., Bruggen, J., Richener, H., Asselbergs, F. A. M., Cerletti, N., Sorg, C., Odink, K., Tarcsay, L., Wiesendanger, W., DeWolf-Peeters, C., Shipman, R. Restin: a novel intermediate filament-associated protein highly expressed in the Reed-Sternberg cells of Hodgkin's disease. EMBO J. 11: 2103-2113, 1992. [PubMed: 1600942] [Full Text: https://doi.org/10.1002/j.1460-2075.1992.tb05269.x]
Delabie, J., Shipman, R., Bruggen, J., De Strooper, B., van Leuven, F., Tarcsay, L., Cerletti, N., Odink, K., Diehl, V., Bilbe, G., De Wolf-Peeters, C. Expression of the novel intermediate filament-associated protein restin in Hodgkin's disease and anaplastic large-cell lymphoma. Blood 80: 2891-2896, 1992. [PubMed: 1450414]
Fukata, M., Watanabe, T., Noritake, J., Nakagawa, M., Yamaga, M., Kuroda, S., Matsuura, Y., Iwamatsu, A., Perez, F., Kaibuchi, K. Rac1 and Cdc42 capture microtubules through IQGAP1 and CLIP-170. Cell 109: 873-885, 2002. [PubMed: 12110184] [Full Text: https://doi.org/10.1016/s0092-8674(02)00800-0]
Griparic, L., Keller, T. C. S., III. Identification and expression of two novel CLIP-170/restin isoforms expressed predominantly in muscle. Biochim. Biophys. Acta 1405: 35-46, 1998. [PubMed: 9784600] [Full Text: https://doi.org/10.1016/s0167-4889(98)00096-2]
Hilliker, C., Delabie, J., Speleman, F., Bilbe, G., Bruggen, J., Van Leuven, F., Van Den Berghe, H. Localization of the gene (RSN) coding for restin, a marker for Reed-Sternberg cells in Hodgkin's disease, to human chromosome band 12q24.3 and YAC cloning of the locus. Cytogenet. Cell Genet. 65: 172-176, 1994. [PubMed: 8222754] [Full Text: https://doi.org/10.1159/000133625]
Irsch, J., Nitsch, S., Hansmann, M.-L., Rajewsky, K., Tesch, H., Diehl, V., Jox, A., Kuppers, R., Radbruch, A. Isolation of viable Hodgkin and Reed-Sternberg cells from Hodgkin disease tissues. Proc. Nat. Acad. Sci. 95: 10117-10122, 1998. [PubMed: 9707610] [Full Text: https://doi.org/10.1073/pnas.95.17.10117]
Larti, F., Kahrizi, K., Musante, L., Hu, H., Papari, E., Fattahi, Z., Bazazzadegan, N., Liu, Z., Banan, M., Garshasbi, M., Wienker, T. F., Ropers, H. H., Galjart, N., Najmabadi, H. A defect in the CLIP1 gene (CLIP-170) can cause autosomal recessive intellectual disability. Europ. J. Hum. Genet. 23: 331-336, 2015. Note: Erratum: Europ. J. Hum. Genet. 23: 416 only, 2015. [PubMed: 24569606] [Full Text: https://doi.org/10.1038/ejhg.2014.13]
Perez, F., Diamantopoulos, G. S., Stalder, R., Kreis, T. E. CLIP-170 highlights growing microtubule ends in vivo. Cell 96: 517-527, 1999. [PubMed: 10052454] [Full Text: https://doi.org/10.1016/s0092-8674(00)80656-x]
Pierre, P., Pepperkok, R., Kreis, T. E. Molecular characterization of two functional domains of CLIP-170 in vivo. J. Cell Sci. 107: 1909-1920, 1994. [PubMed: 7983157] [Full Text: https://doi.org/10.1242/jcs.107.7.1909]
Pierre, P., Scheel, J., Rickard, J. E., Kreis, T. E. CLIP-170 links endocytic vesicles to microtubules. Cell 70: 887-900, 1992. [PubMed: 1356075] [Full Text: https://doi.org/10.1016/0092-8674(92)90240-d]