Alternative titles; symbols
HGNC Approved Gene Symbol: ELMO2
SNOMEDCT: 764100007;
Cytogenetic location: 20q13.12 Genomic coordinates (GRCh38): 20:46,366,050-46,406,615 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q13.12 | Vascular malformation, primary intraosseous | 606893 | Autosomal recessive | 3 |
ELMO proteins, such as ELMO2, are homologs of the C. elegans Ced12 protein, which is required for apoptotic cell engulfment and cell migration. ELMO proteins have no apparent enzymatic activity and exert their biologic functions through interactions with various plasma membrane-associated and cytosolic proteins. In general, ELMO proteins are recruited to the plasma membrane via interacting proteins for efficient activation of downstream effectors (summary by Sun et al., 2015).
The C. elegans genes Ced2, Ced5, and Ced10 and their mammalian homologs CRK (164762), DOCK1 (601403), and RAC1 (602048), respectively, mediate cytoskeletal rearrangements during phagocytosis of apoptotic cells and cell motility. Gumienny et al. (2001) identified Ced12, an additional member of the C. elegans signaling pathway, and mouse and human Ced12 homologs, which they termed ELMO1 (606420), ELMO2, and ELMO3 (606422). They obtained a full-length human cDNA encoding ELMO2 by searching an EST database. The predicted 722-amino acid ELMO2 polypeptide is 44% similar to C. elegans Ced12, 75% identical to ELMO1, and 98% identical to mouse Elmo2. Computer analysis predicted that ELMO1 and ELMO2 are soluble cytoplasmic proteins.
By genomic sequence analysis, Gumienny et al. (2001) mapped the ELMO2 gene to chromosome 20.
Gross (2016) mapped the ELMO2 gene to chromosome 20q13.12 based on an alignment of the ELMO2 sequence (GenBank AF417861) with the genomic sequence (GRCh38).
Katoh and Negishi (2003) demonstrated that RHOG (179505) interacts directly with ELMO2 in a GTP-dependent manner and forms a ternary complex with DOCK180 to induce activation of RAC1. The RHOG-ELMO2-DOCK180 pathway is required for activation of RAC1 and cell spreading mediated by integrin, as well as for neurite outgrowth induced by nerve growth factor. Katoh and Negishi (2003) concluded that RHOG activates RAC1 through ELMO and DOCK180 to control cell morphology.
Hiramoto-Yamaki et al. (2010) showed that EPHA2 (176946) interacted with ephexin-4 (ARHGEF16; 618871) in MDA-MB-231 human breast cancer cells, thereby promoting cell migration and invasion. Ephexin-4 acted as a GEF for RHOG downstream of EPHA2 and interacted with RHOG to activate it. Activated RHOG bound ELMO2 and recruited a ternary complex of ELMO2, DOCK4 (607679), and EPHA2 to the plasma membrane in MDA-MB-231 cells. DOCK4 promoted migration and invasion of MDA-MB-231 cells at tips of cortactin (CTTN; 164765)-rich protrusions through activation of RAC1.
Sun et al. (2015) found that knockdown of Clipr59 (CLIP3; 607382) in a mouse muscle cell line suppressed myoblast fusion. Yeast 2-hybrid screening of a mouse embryonic fibroblast cDNA library with Clipr59 as bait identified Elmo2 as a Clipr59-associated protein. Protein pull-down assays showed that interaction between Clipr59 and Elmo2 was mediated by the atypical pleckstrin (PLEK; 173570) homology domain of Elmo2 and the glu-pro-rich domain of Clipr59. The Clipr59-Elmo2 interaction was regulated by RhoG, and interaction of Clipr59 with Elmo2 enhanced Rac1 activation. Sun et al. (2015) concluded that the CLIPR59-ELMO2 complex is required for myoblast fusion.
Sun et al. (2016) found that overexpression of Elmo2 in mouse adipocytes and rat skeletal muscle cells enhanced insulin-dependent Glut4 (SLC2A4; 138190) membrane translocation. In contrast, knockdown of Elmo2 suppressed Glut4 translocation. Elmo2 was required for insulin-induced Rac1 GTP loading and Akt (AKT1; 164730) membrane association, but not Akt activation, in rat skeletal muscle cells. Sun et al. (2016) concluded that ELMO2 regulates insulin-dependent GLUT4 membrane translocation by modulating RAC1 activity and AKT membrane compartmentalization.
In affected individuals from 4 families with primary intraosseous vascular malformation (VMPI; 606893), Cetinkaya et al. (2016) identified homozygosity for 2 splice site mutations (606421.0001 and 606421.0002) and a 1-bp deletion (606421.0003) in the ELMO2 gene. In a fifth family, the affected individual was homozygous for a complex rearrangement, involving a 5,398-bp deletion and a 330-bp insertion (g.45031191_45037128del5938ins330; GenBank KU680992), that results in deletion of exon 1 along with the transcription start site and surrounding promoter and intronic sequences, as well as insertion of portions of exon 3, intron 3, and intron 1 in reverse orientation. Breakpoint analysis indicated that microhomology-mediated replicative mechanisms might underlie this complex rearrangement. All available parents were heterozygous for the respective mutations, and unaffected sibs were either heterozygous or did not carry the mutation. Analysis of primary fibroblasts from an affected individual showed that absence of ELMO2 correlated with a significant downregulation of binding partner DOCK1, resulting in deficient RAC1-dependent cell migration.
In 3 affected sibs and an unrelated man from 2 consanguineous Turkish families with primary intraosseous vascular malformation (VMPI; 606893), originally reported by Vargel et al. (2002), Cetinkaya et al. (2016) identified homozygosity for a G-A transition at the splice donor site in intron 13 (c.1065+1G-A, NM_133171.4) of the ELMO2 gene. The mutation was present in heterozygosity in the unaffected parents from both families, and unaffected sibs were either heterozygous or did not carry the mutation. Although SNP-based haplotype analysis did not show a common haplotype for the critical region in the 2 Turkish families, intragenic variant analysis revealed an approximately 16-kb consensus haplotype spanning exons 10 to 21 of ELMO2, suggesting that a very distant founder mutation might explain the common mutation in the 2 families; however, recurrent mutations could not be excluded. Primary fibroblasts from an affected individual showed significantly reduced total ELMO2 RNA compared to her unaffected (noncarrier) brother, and levels of ELMO2 in her unaffected heterozygous father were between those of the sister and brother. Endogenous ELMO2 was not detectable in the affected sister's fibroblasts, and endogenous DOCK1 (601403) levels were also significantly lower in her fibroblasts compared to the noncarrier brother's fibroblasts. RT-PCR detected at least 4 aberrantly spliced ELMO2 transcripts in the sister; coexpression of DOCK1 (601403) with the mutant proteins resulted in reduced enhancement of RAC1 (602048) activation, but was nonetheless higher than DOCK1 alone, indicating that the mutants might retain partial activity. Scratch wound assay to assess cellular migration demonstrated that patient fibroblasts migrated twice as slowly as control fibroblasts toward the middle of the wound, and the delay could be partially rescued with wildtype ELMO2. Cetinkaya et al. (2016) suggested that loss of ELMO2, paralleled by a reduction in DOCK1 in human fibroblasts, significantly compromises cell migration.
In 2 sisters from a consanguineous Saudi family with primary intraosseous vascular malformation (VMPI; 606893), Cetinkaya et al. (2016) identified homozygosity for a G-C transversion at the splice acceptor site in intron 19 (c.1802-1G-C, NM_133171.4) of the ELMO2 gene, predicted to disrupt the pleckstrin homology domain that mediates binding to DOCK (see 601403) proteins. The unaffected mother and 3 sisters were heterozygous for the mutation; DNA was unavailable from their deceased father.
In a patient from a consanguineous North American family with primary intraosseous vascular malformation (VMPI; 606893), Cetinkaya et al. (2016) identified homozygosity for a 1-bp deletion (c.2080delC, NM_133171.4) in exon 22 of the ELMO2 gene, causing a frameshift predicted to result in a mutant protein (Leu694TrpfsTer127) that would be 99 amino acids longer than wildtype and would lack the carboxy-terminal proline-rich (PxxP) motif as well as a critical phosphorylation target, trp713.
Cetinkaya, A., Xiong, J. R., Vargel, I., Kosemehmetoglu, K., Canter, H. I., Gerdan, O. F., Longo, N., Alzahrani, A., Camps, M. P. Taskiran, E. Z., Laupheimer, S., Botto, L. D., and 9 others. Loss-of-function mutations in ELMO2 cause intraosseous vascular malformation by impeding RAC1 signaling. Am. J. Hum. Genet. 99: 299-317, 2016. [PubMed: 27476657] [Full Text: https://doi.org/10.1016/j.ajhg.2016.06.008]
Gross, M. B. Personal Communication. Baltimore, Md. 11/30/2016.
Gumienny, T. L., Brugnera, E., Tosello-Trampont, A.-C., Kinchen, J. M., Haney, L. B., Nishiwaki, K., Walk, S. F., Nemergut, M. E., Macara, I. G., Francis, R., Schedl, T., Qin, Y., Van Aelst, L., Hengartner, M. O., Ravichandran, K. S. CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration. Cell 107: 27-41, 2001. [PubMed: 11595183] [Full Text: https://doi.org/10.1016/s0092-8674(01)00520-7]
Hiramoto-Yamaki, N., Takeuchi, S., Ueda, S., Harada, K., Fujimoto, S., Negishi, M. Ephexin4 and EphA2 mediate cell migration through a RhoG-dependent mechanism. J. Cell Biol. 190: 461-477, 2010. [PubMed: 20679435] [Full Text: https://doi.org/10.1083/jcb.201005141]
Katoh, H., Negishi, M. RhoG activates Rac1 by direct interaction with the Dock180-binding protein Elmo. Nature 424: 461-464, 2003. [PubMed: 12879077] [Full Text: https://doi.org/10.1038/nature01817]
Sun, Y., Cote, J.-F., Du, K. Elmo2 is a regulator of insulin-dependent Glut4 membrane translocation. J. Biol. Chem. 291: 16150-16161, 2016. [PubMed: 27226625] [Full Text: https://doi.org/10.1074/jbc.M116.731521]
Sun, Y., Ren, W., Cote, J.-F., Hinds, P. W., Hu, X., Du, K. ClipR-59 interacts with Elmo2 and modulates myoblast fusion. J. Biol. Chem. 290: 6130-6140, 2015. [PubMed: 25572395] [Full Text: https://doi.org/10.1074/jbc.M114.616680]
Vargel, I., Cil, B. E., Er, N., Ruacan, S., Akarsu, A. N., Erk, Y. Hereditary intraosseous vascular malformation of the craniofacial region: an apparently novel disorder. Am. J. Med. Genet. 109: 22-35, 2002. [PubMed: 11932989] [Full Text: https://doi.org/10.1002/ajmg.10282]