Alternative titles; symbolsSLIT-ROBO GAP 3MENTAL DISORDER-ASSOCIATED GAP PROTEIN; MEGAPWAVE-ASSOCIATED RAC GTPase-ACTIVATING PROTEIN; WRPKIAA0411ARHGAP14Other en...
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HGNC Approved Gene Symbol: SRGAP3
Cytogenetic location: 3p25.3 Genomic coordinates (GRCh38): 3:8,980,590-9,363,445 (from NCBI)
▼ Cloning and Expression
By screening for cDNAs with the potential to encode large proteins expressed in brain, Ishikawa et al. (1997) identified a cDNA they designated KIAA0411. KIAA0411 encodes a 650-amino acid protein that is 48.1% identical to C1 RHOGAP (300023). It was predicted to be involved in cell signaling/communication. RT-PCR analysis detected low-level expression of KIAA0411 in brain, lung, kidney, thymus, prostate, testis, and ovary, with little or no expression in all other tissues tested.
The SLIT proteins (e.g., SLIT1; 603742) guide neuronal and leukocyte migration through the Roundabout transmembrane receptors (e.g., ROBO1; 602430). Using a yeast 2-hybrid system to search for proteins interacting with a C-terminal region (amino acids 1455 to 1657) of rat Robo1, Wong et al. (2001) isolated 20 positive clones from a mouse brain cDNA library. Eight of these clones encode a novel family of Rho GTPase-activating proteins (GAPs) that the authors termed SRGAPs. The mouse Srgap1, Srgap2, and Srgap3 proteins correspond to the human KIAA1304 (606523), KIAA0456 (606524), and KIAA0411 proteins, respectively. The SRGAPs contain an FCH domain, a RHOGAP domain, and an SH3 domain. The FCH domain in SRGAP3 is similar to the FCH domains of SRGAP1, SRGAP2, C1 RHOGAP, CDC15, and FER (176942). The centrally located RHOGAP domain in SRGAP3 is highly similar to the RHOGAP domains of SRGAP1, SRGAP2, and C1 RHOGAP. The SH3 domain in SRGAP3 is similar to those in SRGAP1, SRGAP2, C1 RHOGAP, and CSK (124095).
By immunoprecipitation of rat brain cytosol with antibodies against WAVE1 (605035), Soderling et al. (2002) identified interaction between WAVE1 and SRGAP3, which they designated WRP. Northern blot analysis of human tissues detected transcripts of about 8.5 and 7.4 kb expressed predominantly in brain. Soderling et al. (2002) found overlapping expression patterns for WAVE1 and WRP in most brain regions examined.
▼ Gene Function
Soderling et al. (2002) determined that epitope-tagged WRP colocalized with WAVE1 and with actin at the cell cortex of transfected mouse fibroblasts, and they colocalized when expressed in human embryonic kidney cells. Mutation analysis revealed that trp757 in the SH3 domain of WRP and proline-rich sequences within residues 320 to 332 and 420 to 433 of WAVE1 were required for the interaction. Recombinant WRP stimulated intrinsic GTPase activity of Rac, but had no effect on Rho or CDC42 (116952). WRP also reduced neurite outgrowth when transfected into rat cerebellar granular neurons, and this effect was not dependent upon interaction with WAVE1.
By radiation hybrid analysis, Ishikawa et al. (1997) mapped the KIAA0411 gene to chromosome 3. Endris et al. (2002) analyzed a balanced de novo translocation t(X;3)(p11.2;p25) and showed that the chromosome 3 breakpoint at 3p25 involved KIAA0411. By FISH and loss of heterozygosity (LOH) analysis, they further demonstrated that this gene, which they referred to as MEGAP/SRGAP3, resides on 3p25 and is deleted in patients with 3p- syndrome (613792).
Endris et al. (2002) performed molecular analysis in a patient with a balanced de novo translocation t(X;3)(p11.2;p25), hypotonia, and severe mental retardation, features characteristic of 3p- syndrome. The translocation breakpoint on the X chromosome was located outside of any coding region; however, the breakpoint on chromosome 3 interrupted the previously unknown gene which Endris et al. (2002) termed MEGAP (mental disorder-associated GAP protein). MEGAP shares structural and functional similarities with other members of the RhoGAP protein family and is highly expressed in fetal and adult brain tissue. The C-terminal part of MEGAP corresponds to SRGAP3, which was shown by Wong et al. (2001) to play a critical role in the Slit-Robo signal-transduction pathway. Endris et al. (2002) suggested that the phenotype they observed in their patient was caused by a misregulation of a neuronal signal-transduction machinery controlling the correct migration of neurons and their axonal connectivity. They described several MEGAP transcript isoforms and showed that 2 of these represent functional GTPase-activated proteins (GAPs) by an in vitro GAP assay. They proposed that haploinsufficiency of MEGAP/SRGAP3 leads to the abnormal development of neuronal structures that are important for normal cognitive function.
Jones et al. (2009) found a tandem duplication at chromosome 3p25 in a pilocytic astrocytoma (see 137800) that resulted in fusion of exons 1 through 12 of the SRGAP3 gene to exons 10 through 17 of the RAF1 gene (164760). The fusion transcript encodes a deduced protein containing the first 513 N-terminal amino acids of SRGAP3, including the FES (190030)/CIP4 (TRIP10; 604504) homology domain, fused to 318 C-terminal amino acids of RAF1, including the entire RAF1 kinase domain. The fusion protein showed higher activity than wildtype RAF1 in phosphorylation of endogenous Mek1 (MAP2K1; 176872) in mouse fibroblasts, and it conferred anchorage-independent cell growth.