Alternative titles; symbols
HGNC Approved Gene Symbol: WIPF1
Cytogenetic location: 2q31.1 Genomic coordinates (GRCh38) : 2:174,559,574-174,682,913 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q31.1 | Wiskott-Aldrich syndrome 2 | 614493 | Autosomal recessive | 3 |
A major function of WIPF1 is to stabilize WASP (300392) and prevent its degradation, and WASP is almost totally complexed with WIPF1 in T cells (Lanzi et al., 2012).
In an attempt to understand better the function of WASP (300392), which is mutant in Wiskott-Aldrich syndrome (WAS; 301000), Ramesh et al. (1997) used the yeast 2-hybrid system and cloned a novel human gene whose 503-amino acid product interacted with WASP. They named the protein WIP, for WASP-interacting protein.
Lanzi et al. (2012) reported that the WIPF1 protein has 2 N-terminal WASP homology-2 (WH2) domains that interact with actin (see 102560), followed by a cortactin (CTTN; 164765)-interacting domain, an NCK (NCK1; 600508)/CRKL (602007)-interacting domain, and a C-terminal WASP/N-WASP (WASL; 605056)-interacting domain.
Lanzi et al. (2012) reported that the WIPF1 gene contains 8 exons. The first exon is noncoding.
Gross (2012) mapped the WIPF1 gene to chromosome 2q31.1 based on an alignment of the WIPF1 sequence (GenBank BC110288) with the genomic sequence (GRCh37).
Ramesh et al. (1997) showed that overexpression of WIP increased F-actin (see 102610) content and induced actin-containing structures in a human B-cell line, suggesting an important role for WIP in the organization of the actin cytoskeleton.
Sasahara et al. (2002) showed that the adaptor protein CRKL binds directly to WIP and that, following T-cell receptor ligation, a CRKL-WIP-WASP complex is recruited by ZAP70 (176947) to lipid rafts and immunologic synapses.
Using mass spectrometric analysis, Scott et al. (2002) identified 25 potential binding partners in a human monocyte cell line for the SH3 domain of HCK (142370). Analysis with purified proteins and in intact cells confirmed the interactions with WIP, WASP, and ELMO1 (606420). Scott et al. (2002) concluded that WIP, WASP, and ELMO1 may be activators or effectors of HCK.
Weisswange et al. (2009) analyzed the dynamics of N-WASP, WIP, GRB2 (108355), and NCK, which are required to stimulate actin-related protein (ARP)2/3 complex (see 604221 and 604222)-dependent actin-based motility of vaccinia virus, using fluorescence recovery after photobleaching. Weisswange et al. (2009) showed that all 4 proteins are rapidly exchanging, albeit at different rates, and that the turnover of N-WASP depends on its ability to stimulate ARP2/3 complex-mediated actin polymerization. Conversely, disruption of the interaction of N-WASP with GRB2 and/or the barbed ends of actin filaments increases its exchange rate and results in a faster rate of virus movement. Weisswange et al. (2009) suggested that the exchange rate of N-WASP controls the rate of ARP2/3 complex-dependent actin-based motility by regulating the extent of actin polymerization by antagonizing filament capping.
In a Moroccan infant with Wiskott-Aldrich syndrome-2 (WAS2; 614493), Lanzi et al. (2012) identified a homozygous ser434-to-ter (S434X; 602357.0001) mutation in the WIPF1 gene. The patient's parents, who were consanguineous, were heterozygous for the mutation.
In 4 patients from a large multigenerational consanguineous Saudi Arabian kindred with WAS2, Al-Mousa et al. (2017) identified a homozygous nonsense mutation in the WIPF1 gene (Q237X; 602357.0002). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.
Anton et al. (2002) generated Wip -/- mice. These mice had normal lymphocyte development, but their T lymphocytes failed to proliferate, secrete interleukin-2 (IL2; 147680), increase their F-actin content, polarize, and extend protrusions following T-cell receptor (see 186880) ligation. In contrast, B cells had enhanced proliferation and CD69 (107273) activation marker expression following B-cell receptor ligation. B cells also mounted normal antibody responses to T-cell-independent antigens. Serum IgM and IgE levels were elevated in the mutant mice, but IgA and IgG levels were normal. Both B and T cells from Wip-deficient mice showed a profound defect in their subcortical actin filament networks. Anton et al. (2002) proposed that WIP is important for immunologic synapse formation and T-cell activation.
Kettner et al. (2004) found that mouse Wip -/- bone marrow-derived mast cells (BMMCs) developed normally, but IgE-mediated anaphylaxis, as measured by plasma histamine, was greatly diminished, as was Fcer1 (see 147140)-mediated Il6 (147620) production. After Fcer1 ligation, Wip associated with Syk (600085) in wildtype BMMCs; however, Syk protein expression, but not mRNA expression, was severely reduced in mutant mice. Expression levels in mutant BMMCs could be restored by proteasome and calpain inhibitors, suggesting that WIP inhibits the degradation of SYK in mast cells. Electron microscopy demonstrated an impairment of actin polymerization-dependent spreading, protrusion formation, F-actin content change, and cell shape change in Wip -/- BMMCs. Kettner et al. (2004) concluded that WIP regulates FCER1-mediated mast cell activation by regulating SYK levels and actin cytoskeleton rearrangement.
In an 11-day-old Moroccan girl with Wiskott-Aldrich syndrome-2 (WAS2; 614493), Lanzi et al. (2012) identified a homozygous c.1301C-G transversion in exon 6 of the WIPF1 gene, resulting in a ser434-to-ter (S434X) substitution. The patient was born to consanguineous parents who had previously lost a daughter at age 4 months with recurrent infections. Both parents were heterozygous for the mutation and showed approximately half the normal level of WIPF1, suggesting a gene dosage effect. Unrelated cord blood transplantation at age 4.5 months restored immunologic function in the patient, and she was healthy 16 months after the procedure.
In 4 patients from a large multigenerational consanguineous Saudi Arabian kindred with Wiskott-Aldrich syndrome-2 (WAS2; 614493), Al-Mousa et al. (2017) identified a homozygous C-T transition in exon 6 of the WIPF1 gene, resulting in a gln237-to-ter (Q237X) substitution. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. (In the article by Al-Mousa et al. (2017), there was a discrepancy in the nucleotide change, which was cited as c.709C-T in the text, but as 873C-T in Fig. E2.)
Al-Mousa, H., Hawwari, A., Al-Ghonaium, A., Al-Saud, B., Al-Dhekri, H., Al-Muhsen, S., Elshorbagi, S., Dasouki, M., El-Baik, L., Alseraihy, A., Ayas, M., Arnaout, R. Hematopoietic stem cell transplantation corrects WIP deficiency. (Letter) J. Allergy Clin. Immun. 139: 1039-1040, 2017. [PubMed: 27742395] [Full Text: https://doi.org/10.1016/j.jaci.2016.08.036]
Anton, I. M., de la Fuente, M. A., Sims, T. N., Freeman, S., Ramesh, N., Hartwig, J. H., Dustin, M. L., Geha, R. S. WIP deficiency reveals a differential role for WIP and the actin cytoskeleton in T and B cell activation. Immunity 16: 193-204, 2002. [PubMed: 11869681] [Full Text: https://doi.org/10.1016/s1074-7613(02)00268-6]
Gross, M. B. Personal Communication. Baltimore, Md. 2/23/2012.
Kettner, A., Kumar, L., Anton, I. M., Sasahara, Y., de la Fuente, M., Pivniouk, V. I., Falet, H., Hartwig, J. H., Geha, R. S. WIP regulates signaling via the high affinity receptor for immunoglobulin E in mast cells. J. Exp. Med. 199: 357-368, 2004. [PubMed: 14757742] [Full Text: https://doi.org/10.1084/jem.20030652]
Lanzi, G., Moratto, D., Vairo, D., Masneri, S., Delmonte, O., Paganini, T., Parolini, S., Tabellini, G., Mazza, C., Savoldi, G., Montin, D., Martino, S., and 9 others. A novel primary human immunodeficiency due to deficiency in the WASP-interacting protein WIP. J. Exp. Med. 209: 29-34, 2012. [PubMed: 22231303] [Full Text: https://doi.org/10.1084/jem.20110896]
Ramesh, N., Anton, I. M., Hartwig, J. H., Geha, R. S. WIP, a protein associated with Wiskott-Aldrich syndrome protein, induces actin polymerization and redistribution in lymphoid cells. Proc. Nat. Acad. Sci. 94: 14671-14676, 1997. [PubMed: 9405671] [Full Text: https://doi.org/10.1073/pnas.94.26.14671]
Sasahara, Y., Rachid, R., Byrne, M. J., de la Fuente, M. A., Abraham, R. T., Ramesh, N., Geha, R. S. Mechanism of recruitment of WASP to the immunological synapse and of its activation following TCR ligation. Molec. Cell 10: 1269-1281, 2002. [PubMed: 12504004] [Full Text: https://doi.org/10.1016/s1097-2765(02)00728-1]
Scott, M. P., Zappacosta, F., Kim, E. Y., Annan, R. S., Miller, W. T. Identification of novel SH3 domain ligands for the Src family kinase Hck: Wiskott-Aldrich syndrome protein (WASP), WASP-interacting protein (WIP), and ELMO1. J. Biol. Chem. 277: 28238-28246, 2002. [PubMed: 12029088] [Full Text: https://doi.org/10.1074/jbc.M202783200]
Weisswange, I., Newsome, T. P., Schleich, S., Way, M. The rate of N-WASP exchange limits the extent of ARP2/3-complex-dependent actin-based motility. Nature 458: 87-91, 2009. [PubMed: 19262673] [Full Text: https://doi.org/10.1038/nature07773]