Alternative titles; symbols
HGNC Approved Gene Symbol: ARHGEF6
Cytogenetic location: Xq26.3 Genomic coordinates (GRCh38): X:136,665,550-136,780,932 (from NCBI)
Rho guanine nucleotide exchange factors (GEFs) belong to a family of cytoplasmic proteins that activate the Ras-like family of Rho proteins by exchanging bound GDP for GTP.
p21-activated kinases, or PAKs (see PAK1; 602590), bind to and are activated by Rho family GTPases, such as CDC42 (116952) and RAC (see RAC1; 602048). PAKs are implicated in the regulation of gene expression, cytoskeletal architecture, and apoptosis. By screening rat tissue extracts for binding to PAK1, peptide microsequencing, and primer walking, Manser et al. (1998) isolated a rat cDNA encoding Pixa (PAK-interacting exchange factor-alpha). Pixa is highly homologous to the human myoblast cDNA KIAA0006 identified by Nomura et al. (1994). By RT-PCR of human placenta, Manser et al. (1998) identified 3 additional N-terminal residues of KIAA0006, or human PIXA. Sequence analysis predicted that the 776-amino acid PIXA protein contains an N-terminal SH3 domain, a Dbl-homology (DH) domain, and a pleckstrin homology (PH) domain, suggestive of a Rho GEF. Northern blot analysis detected an approximately 5.0-kb transcript in heart, muscle, thymus, spleen, and placenta, with lower expression in brain, prostate, and testis, and little or no expression in lung, liver, and kidney.
Kutsche et al. (2000) used YAC, PAC, and cosmid clones to isolate a DNA sequence from a breakpoint region on Xq26 in a patient with severe mental retardation (see 300436) who had an X;21 translocation. They identified a 6,017-bp cDNA sequence encoding the 776-amino acid PIXA protein. Kutsche et al. (2000) noted that the ARHGEF6 polypeptide contains several evolutionarily conserved regions frequently found in other Rho GEF family members; however, the N-terminal calponin homology (CH) domain is unique to ARHGEF6. There were no significant differences in the expression pattern in different parts of normal brain. The translocation breakpoint in the patient was thought to be located between exons 10 and 11.
By immunofluorescence microscopy, Manser et al. (1998) showed that the SH3 domain of PIXA is required for recruitment of PAK1 to CDC42-driven focal complexes. Functional analysis demonstrated that PIXA acts as a RAC1 GEF and can induce membrane ruffling.
Kutsche et al. (2000) stated that ARHGEF6 was the third X-linked mental retardation gene, after OPHN1 (300127) and PAK3 (300142), whose protein was found to be involved in the Rho GTPase cycle, which mediates organization of the cytoskeleton, cell shape, and motility.
Rosenberger et al. (2003) used the full-length coding region of ARHGEF6 as bait in yeast 2-hybrid screens and identified PARVB (608121) as a novel binding partner. ARHGEF6 and PARVB were shown by immunofluorescence to colocalize at the cell periphery to lamellipodia and ruffles in well-spread and actively spreading cells adhered to fibronectin (see 135600). In addition, interaction of ARHGEF6 with ARHGEF7 (605477), a close homolog of ARHGEF6, was confirmed. In in vivo assays, 2 ARHGEF6 mutations previously identified in patients with X-linked nonspecific mental retardation abolished interaction of ARHGEF6 with PARVB. These data suggested that both the N-terminal CH and C-terminal coiled-coil domains may be necessary for the ARHGEF6-PARVB binding. PARVB interacts with integrin-linked kinase (ILK; 602366) and is involved in the early stage of cell-substrate interaction through integrins. Rosenberger et al. (2003) suggested that ARHGEF6 may be involved in integrin-mediated signaling leading to activation of the GTPases RAC1 and/or CDC42.
Kutsche et al. (2000) and Lower and Gecz (2001) determined that the PIXA gene contains 22 exons.
By radiation hybrid analysis, Nomura et al. (1994) mapped the PIXA gene to the X chromosome.
Exclusion Studies
The mutation in the ARHGEF6 gene that was identified by Kutsche et al. (2000) in the family with nonspecific X-linked mental retardation (MRX46; 300436) reported by Yntema et al. (1998) has been reclassified as a variant of unknown significance (300267.0001).
Lower and Gecz (2001) performed mutation analysis in individuals with Borjeson-Forssman-Lehmann syndrome (BFLS; 301900) or MRX27, both of which map to the same region of Xq as the ARHGEF6 gene (Gedeon et al., 1996), and detected no ARHGEF6 abnormality.
This variant, formerly titled MENTAL RETARDATION, X-LINKED 46, has been reclassified based on a review of the ExAC database by Hamosh (2018).
In affected males in a large Dutch family with nonspecific X-linked mental retardation (MRX46; 300436), Kutsche et al. (2000) identified a mutation in the ARHGEF6 gene. The base change IVS1-11T-C had a marginal effect on the predicted splicing efficiency but was not detected in 170 control chromosomes. In affected males, RT-PCR amplification demonstrated products of 2 different sizes: a larger amplicon corresponding to the wildtype fragment, and a smaller amplicon in which exon 1 was spliced to exon 3. Thus, all mentally retarded males in the MRX46 family exhibited enhanced skipping of exon 2.
Hamosh (2018) found that the IVS1-11T-C variant (rs140322310) was present in 53 hemizygotes in the ExAC database (November 21, 2018), suggesting that the variant is not pathogenic.
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Gedeon, A. K., Glass, I. A., Connor, J. M., Mulley, J. C. Genetic localisation of MRX27 to Xq24-26 defines another discrete gene for non-specific X-linked mental retardation. Am. J. Med. Genet. 64: 121-124, 1996. [PubMed: 8826461] [Full Text: https://doi.org/10.1002/(SICI)1096-8628(19960712)64:1<121::AID-AJMG20>3.0.CO;2-O]
Hamosh, A. Personal Communication. Baltimore, Md. 11/21/2018.
Kutsche, K., Yntema, H., Brandt, A., Jantke, I., Nothwang, H. G., Orth, U., Boavida, M. G., David, D., Chelly, J., Fryns, J.-P., Moraine, C., Ropers, H.-H., Hamel, B. C. J., van Bokhoven, H., Gal, A. Mutations in ARHGEF6, encoding a guanine nucleotide exchange factor for Rho GTPases, in patients with X-linked mental retardation. Nature Genet. 26: 247-250, 2000. [PubMed: 11017088] [Full Text: https://doi.org/10.1038/80002]
Lower, K. M., Gecz, J. Characterization of ARHGEF6, a guanine nucleotide exchange factor for Rho GTPases and a candidate gene for X-linked mental retardation: mutation screening in Borjeson-Forssman-Lehmann syndrome and MRX27. Am. J. Med. Genet. 100: 43-48, 2001. [PubMed: 11337747] [Full Text: https://doi.org/10.1002/ajmg.1189]
Manser, E., Loo, T.-H., Koh, C.-G., Zhao, Z.-S., Chen, X.-Q., Tan, L., Tan, I., Leung, T., Lim, L. PAK kinases are directly coupled to the PIX family of nucleotide exchange factors. Molec. Cell 1: 183-192, 1998. [PubMed: 9659915] [Full Text: https://doi.org/10.1016/s1097-2765(00)80019-2]
Nomura, N., Miyajima, N., Sazuka, T., Tanaka, A., Kawarabayashi, Y., Sato, S., Nagase, T., Seki, N., Ishikawa, K., Tabata, S. Prediction of the coding sequences of unidentified human genes. I. The coding sequences of 40 new genes (KIAA0001-KIAA0040) deduced by analysis of randomly sampled cDNA clones from human immature myeloid cell line, KG-1. DNA Res. 1: 27-35, 1994. Note: Erratum: DNA Res. 2: 210 only, 1995. [PubMed: 7584026] [Full Text: https://doi.org/10.1093/dnares/1.1.27]
Rosenberger, G., Jantke, I., Gal, A., Kutsche, K. Interaction of alpha-PIX (ARHGEF6) with beta-parvin (PARVB) suggests an involvement of alpha-PIX in integrin-mediated signaling. Hum. Molec. Genet. 12: 155-167, 2003. [PubMed: 12499396] [Full Text: https://doi.org/10.1093/hmg/ddg019]
Yntema, H. G., Hamel, B. C., Smits, A. P., van Roosmalen, T., van den Helm, B., Kremer, H., Ropers, H. H., Smeets, D. F., van Bokhoven, H. Localisation of a gene for non-specific X linked mental retardation (MRX46) to Xq25-q26. J. Med. Genet. 35: 801-805, 1998. [PubMed: 9783701] [Full Text: https://doi.org/10.1136/jmg.35.10.801]