Alternative titles; symbols
HGNC Approved Gene Symbol: EFNA4
Cytogenetic location: 1q21.3 Genomic coordinates (GRCh38): 1:155,063,740-155,069,553 (from NCBI)
Proteins in the LERK subfamily of ligands, called ephrins, bind to members of the EPH group of receptor tyrosine kinases. The various ephrins are characterized by sequence similarities and the fact that they are attached to the cell membrane by glycosylphosphatidylinositol (GPI) anchors or by a single transmembrane domain (Cerretti et al., 1996). See 179610 for additional information on ephrins and the Eph receptor family.
Using the receptor tyrosine kinase HEK (EPHA3; 179611) as bait to screen a human T-lymphoma HSB-2 cDNA expression library, Kozlosky et al. (1995) cloned LERK4. The deduced 201-amino acid LERK4 protein has a predicted N-terminal signal sequence, an extracellular receptor-binding domain, a spacer region, and a hydrophobic C terminus. The receptor-binding domain has an N-glycosylation site and 6 cysteines predicted to form disulfide bonds, and the C terminus shares structural similarity with GPI-linked proteins. Northern blot analysis detected a 1.4-kb LERK4 transcript in human adult spleen, prostate, ovary, small intestine, and colon and in fetal heart, lung, and kidney.
Cerretti and Nelson (1998) reported that the mouse Efna4 gene has 4 exons. The gene structures of human EFNA2 (602756) and mouse Efna4, Efna3 (601381), and Efnb1 (300035) are conserved through the first 3 exons.
Using fluorescence in situ hybridization, Cerretti et al. (1996) mapped the EPLG4 gene to a cluster on chromosome 1q21-q22, together with EPLG1 (EFNA1; 191164) and EPLG3 (EFNA3; 601381). By interspecific backcross analysis, they mapped the mouse EPLG4 homolog (Epl4) to the central region of mouse chromosome 3.
By analyzing binding kinetics, Kozlosky et al. (1995) found that LERK4 had a single class of binding sites for HEK, but a biphasic binding curve with high- and low-affinity binding components for ELK (EPHB1; 600600).
Associations Pending Confirmation
Merrill et al. (2006) screened 81 DNA samples from patients with nonsyndromic coronal craniosynostosis (see CRS1; 123100) for variation in the coding sequence of EFNA4 and identified 3 heterozygous variants in 3 patients with unicoronal synostosis: 2 were missense mutations, H60Y (rs148289726) and P117T (rs143886639), and the third was a frameshift indel mutation (471_472delCCinsA). Each variant was also present in a clinically unaffected parent, but none were found in 370 northern European control samples or in 151 additional unrelated craniosynostosis patients who had either syndromic features or a different combination of affected cranial sutures. Transfection studies in COS-7 cells showed complete (98%) loss of binding for the P117T mutant and partial (65%) loss for the H60Y mutant compared to wildtype. Using patient fibroblasts, Merrill et al. (2006) demonstrated that the frameshift mutation is expressed in an alternatively spliced minor isoform of EFNA4.
Cerretti, D. P., Lyman, S. D., Kozlosky, C. J., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Valentine, V., Kirstein, M. N., Shapiro, D. N., Morris, S. W. The genes encoding the Eph-related receptor tyrosine kinase ligands LERK-1 (EPLG1, Epl1), LERK-3 (EPLG3, Epl3), and LERK-4 (EPLG4, Epl4) are clustered on human chromosome 1 and mouse chromosome 3. Genomics 33: 277-282, 1996. [PubMed: 8660976] [Full Text: https://doi.org/10.1006/geno.1996.0192]
Cerretti, D. P., Nelson, N. Characterization of the genes for mouse LERK-3/Ephrin-A3 (Epl3), mouse LERK-4/Ephrin-A4 (Epl4), and human LERK-6/Ephrin-A2 (EPLG6): conservation of intron/exon structure. Genomics 47: 131-135, 1998. [PubMed: 9465306] [Full Text: https://doi.org/10.1006/geno.1997.5088]
Kozlosky, C. J., Maraskovsky, E., McGrew, J. T., VandenBos, T., Teepe, M., Lyman, S. D., Srinivasan, S., Fletcher, F. A., Gayle, R. B., III, Cerretti, D. P., Beckmann, M. P. Ligands for the receptor tyrosine kinases hek and elk: isolation of cDNAs encoding a family of proteins. Oncogene 10: 299-306, 1995. [PubMed: 7838529]
Merrill, A. E., Bochukova, E. G., Brugger, S. M., Ishii, M., Pilz, D. T., Wall, S. A., Lyons, K. M., Wilkie, A. O. M., Maxson, R. E., Jr. Cell mixing at a neural crest-mesoderm boundary and deficient ephrin-Eph signaling in the pathogenesis of craniosynostosis. Hum. Molec. Genet. 15: 1319-1328, 2006. [PubMed: 16540516] [Full Text: https://doi.org/10.1093/hmg/ddl052]