Alternative titles; symbols
HGNC Approved Gene Symbol: ARHGAP31
Cytogenetic location: 3q13.32-q13.33 Genomic coordinates (GRCh38) : 3:119,294,383-119,420,714 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q13.32-q13.33 | Adams-Oliver syndrome 1 | 100300 | Autosomal dominant | 3 |
Rho GTPases regulate a variety of cellular functions, including proliferation and cytoskeletal dynamics, by cycling between inactive GDP-bound and active GTP-bound forms. This cycle is regulated by guanine nucleotide exchange factors and GTPase-activating proteins (GAPs). CDGAP is a GAP for the Rho GTPases CDC42 (116952) and RAC1 (602048), but not RhoA (ARHA; 165390) (Tcherkezian et al., 2006).
By yeast 2-hybrid screening using a constitutively active Cdc42 mutant as bait, Lamarche-Vane and Hall (1998) cloned mouse Cdgap. The deduced 820-amino acid mouse protein has a calculated molecular mass of 89.6 kD. It is rich in both serines and charged amino acids and has a RhoGAP domain at its N terminus and potential protein kinase C (see 176960) phosphorylation sites and 5 proline-rich SH3-binding motifs at its C terminus. Northern blot analysis of mouse tissues revealed ubiquitous expression, with highest levels in heart and lung.
By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (1999) cloned KIAA1204. The deduced protein contains 1,445 amino acids. RT-PCR ELISA detected moderate expression in all adult and fetal tissues examined except testis, in which KIAA1204 was not expressed. Moderate expression was also present in all specific brain regions examined.
Tcherkezian et al. (2006) noted that long and short Cdgap isoforms are present in mouse. By database analysis, they identified KIAA1204 as human CDGAP. The 1,444-amino acid human CDGAP protein shares 76% identity with the 1,425-amino acid long form of mouse Cdgap. Human CDGAP contains an N-terminal RhoGAP domain, followed by a long stretch rich in both serines and charged residues. It has 2 central proline-rich sequences with consensus SH3-binding sites, 1 of which is conserved in mouse. Northern blot analysis of human fetal tissues detected a 7.5-kb transcript in all tissues examined, with highest levels in heart and muscle. A 1.35-kb transcript was also detected in heart and muscle, but not other fetal tissues examined. Immunoblot analysis revealed 250-, 155-, and 90-kD proteins in human fetal tissues. The 250-kD isoform was highly expressed in heart and muscle, whereas the 155- and 90-kD isoforms were mainly expressed in brain and kidney, respectively.
Southgate et al. (2011) analyzed ARHGAP31 transcript expression in human fetal tissues and found abundant and ubiquitous expression in all tissues examined. Analysis of mouse embryos during early development showed that at 9.5 days postconception (dpc), the strongest expression is in the developing heart, with regional localization to the ventral walls of the primitive ventricle and primitive atrium. By 10.5 dpc, Arhgap31 expression becomes largely restricted to the developing ventricle, and expression in the primitive atrium becomes localized to its outer wall. At 11.5 dpc, Arhgap31 expression is primarily in the surface ectoderm, and strong expression overlies the entire heart field, symmetrical regions of the head and flank, and the apical regions of the hand and foot plates.
Southgate et al. (2011) stated that the ARHGAP31 gene contains 12 exons.
Southgate et al. (2011) identified the ARHGAP31 gene within a region on chromosome 3q13.31-q13.33 identified by linkage analysis.
Lamarche-Vane and Hall (1998) showed that mouse Cdgap had GAP activity against Rac1 and Cdc42, but not RhoA, in vitro, and that it downregulated Cdc42 and Rac1 in vivo.
Tcherkezian et al. (2006) found that, similar to mouse Cdgap, human CDGAP was active in vitro and in vivo on both CDC42 and RAC1, but not RhoA, and it was phosphorylated in vivo on serine and threonine residues. Like mouse Cdgap, human CDGAP interacted with ERK1 (MAPK3; 601795) and ERK2 (MAPK1; 176948), but it did so via a docking site distinct from the DEF domain in mouse Cdgap. Overexpression of CDGAP in COS-7 cells resulted in membrane blebbing, a feature typically associated with apoptosis.
Using yeast 2-hybrid and coimmunoprecipitation analyses, Danek et al. (2007) showed that CDGAP bound both glycogen synthase kinase-3A (GSK3A; 606784) and GSK3B (605004) in human and mouse cells. GSK3 phosphorylated CDGAP both in vitro and in vivo on thr776 within the proline-rich domain.
In 2 families with congenital scalp defects and distal limb reduction anomalies mapping to chromosome 3q13 (Adams-Oliver syndrome-1, AOS1; 100300), Southgate et al. (2011) sequenced 4 candidate genes and identified heterozygosity for 2 different truncating mutations in the ARHGAP31 gene (610911.0001 and 610911.0002, respectively) that segregated with disease in each family. Functional analysis revealed that both mutations behave as dominant gain-of-function alleles.
In affected members of a large 5-generation family with congenital scalp defects and distal limb reduction anomalies (AOS1; 100300), originally reported by Bonafede and Beighton (1979), Southgate et al. (2011) identified heterozygosity for a c.2047C-T transition (c.2047C-T, NM_020754.2) in exon 12 of the ARHGAP31 gene, resulting in a gln683-to-ter (Q683X) substitution. The mutation was not found in unaffected family members or in more than 2,000 control chromosomes. Quantitative RT-PCR of RNA extracted from patient and control lymphoblasts demonstrated stability of the mutant transcript compared to wildtype. Functional analysis in HEK293 cells revealed marked augmentation of GAP activity upon Cdc42 by the truncated protein relative to wildtype, resulting in a significant downregulation of the active GTPase. A significant decrease in the proliferative ability of G683X primary dermal fibroblasts compared to wildtype was observed. In a wound-healing migration assay, fibroblasts heterozygous for Q683X migrated at a significantly faster rate than similar wildtype fibroblasts, suggestive of altered cell motility.
In affected members of a large 4-generation family with congenital scalp defects and distal limb reduction anomalies (AOS1; 100300), originally reported by Verdyck et al. (2006), Southgate et al. (2011) identified heterozygosity for a 1-bp deletion (c.3260delA, NM_020754.2) in exon 12 of the ARHGAP31 gene, predicted to cause a frameshift and premature termination of the protein (Lys1087SerfsTer4). The mutation was not found in unaffected family members or in more than 2,000 control chromosomes. Functional analysis in HEK293 cells revealed marked augmentation of GAP activity upon Cdc42 by the truncated protein relative to wildtype, resulting in a significant downregulation of the active GTPase.
Bonafede, R. P., Beighton, P. Autosomal dominant inheritance of scalp defects with ectrodactyly. Am. J. Med. Genet. 3: 35-41, 1979. [PubMed: 474617] [Full Text: https://doi.org/10.1002/ajmg.1320030109]
Danek, E. I., Tcherkezian, J., Triki, I., Meriane, M., Lamarche-Vane, N. Glycogen synthase kinase-3 phosphorylates CdGAP at a consensus ERK 1 regulatory site. J. Biol. Chem. 282: 3624-3631, 2007. [PubMed: 17158447] [Full Text: https://doi.org/10.1074/jbc.M610073200]
Lamarche-Vane, N., Hall, A. CdGAP, a novel proline-rich GTPase-activating protein for Cdc42 and Rac. J. Biol. Chem. 273: 29172-29177, 1998. [PubMed: 9786927] [Full Text: https://doi.org/10.1074/jbc.273.44.29172]
Nagase, T., Ishikawa, K., Kikuno, R., Hirosawa, M., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6: 337-345, 1999. [PubMed: 10574462] [Full Text: https://doi.org/10.1093/dnares/6.5.337]
Southgate, L., Machado, R. D., Snape, K. M., Primeau, M., Dafou, D., Ruddy, D. M., Branney, P. A., Fisher, M., Lee, G. J., Simpson, M. A., He, Y., Bradshaw, T. Y., and 9 others. Gain-of-function mutations of ARHGAP31, a Cdc42/Rac1 GTPase regulator, cause syndromic cutis aplasia and limb anomalies. Am. J. Hum. Genet. 88: 574-585, 2011. [PubMed: 21565291] [Full Text: https://doi.org/10.1016/j.ajhg.2011.04.013]
Tcherkezian, J., Triki, I., Stenne, R., Danek, E. I., Lamarche-Vane, N. The human orthologue of CdGAP is a phosphoprotein and a GTPase-activating protein for Cdc42 and Rac1 but not RhoA. Biol. Cell 98: 445-456, 2006. [PubMed: 16519628] [Full Text: https://doi.org/10.1042/BC20050101]
Verdyck, P., Blaumeiser, B., Holder-Espinasse, M., Van Hul, W., Wuyts, W. Adams-Oliver syndrome: clinical description of a four-generation family and exclusion of five candidate genes. Clin. Genet. 69: 86-92, 2006. [PubMed: 16451141] [Full Text: https://doi.org/10.1111/j.1399-0004.2006.00552.x]