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Gene Review

GFRA1  -  GDNF family receptor alpha 1

Homo sapiens

Synonyms: GDNF family receptor alpha-1, GDNF receptor alpha-1, GDNFR, GDNFR-alpha-1, GDNFRA, ...
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Disease relevance of GFRA1


High impact information on GFRA1

  • Germline mutations of the RET ligand GDNF are not sufficient to cause Hirschsprung disease [6].
  • The active receptor complex for GDNF includes the receptor tyrosine kinase Ret and a novel class of glycosylphosphatidylinositol-linked receptors, called GDNF family receptor alpha s [7].
  • GAS1, an apparently unrelated protein, exhibits homology to GFR alpha and thus we hypothesize that GAS1 can serve as an alternative receptor for GFLs [8].
  • We propose that the relative expression and localization of the two remote receptors, GFR alpha and GAS1, on the membranes of neuronal and glial cells determines whether these cells survive or undergo apoptotic death [8].
  • Genes in this area (GFRA1, ADORA2L, FGR2, EMX2, and HMX2) can be considered promising positional candidates for genetic association studies of respiratory control during sleep [9].

Chemical compound and disease context of GFRA1


Biological context of GFRA1

  • We have mapped GFRA1 to human chromosome 10q25, isolated human and mouse genomic clones, determined the gene's intron-exon boundaries, isolated a highly polymorphic microsatellite marker adjacent to exon 7, and scanned for GFRA1 mutations in a large panel of HSCR patients [1].
  • To examine the expression levels of GFR alpha-1, we cloned a short form of the human GFR alpha-1 gene with a 15-bp deletion by screening a human adult substantia nigra cDNA library [12].
  • We have exploited sequence and functional divergences between the ectodomains of mammalian and amphibian RET molecules to map binding determinants in the human RETECD responsible for its interaction with the GDNF-GFR alpha 1 complex by homologue-scanning mutagenesis [13].
  • Dimerization was achieved experimentally by constructing a double mutant receptor with a MEN2A mutation (Cys634Arg) in addition to the MEN2B mutation, and by chronic exposure of RetMEN2B-expressing cells to the Ret ligand GDNF [14].
  • Alternatively, a preassociated complex between GFRalpha and Ret could form the binding site for the GDNF family ligand [15].

Anatomical context of GFRA1


Associations of GFRA1 with chemical compounds

  • The enhanced expression and associated increase in adhesive and invasive abilities were inhibited by blocking the GDNF receptor or the integrin beta1 subunit [11].

Physical interactions of GFRA1


Regulatory relationships of GFRA1

  • To ascertain whether the biological effects of ret mutations are modulated by GDNF, we have investigated the responsiveness to GDNF of ret mutants in cell lines coexpressing GDNFR-alpha and MEN2A-, MEN2B-, FMTC-, or HSCR-associated ret mutants [18].

Other interactions of GFRA1

  • Cross-linking experiments have indicated that the RETECD makes direct contacts with both the GDNF ligand and GFR alpha 1 molecule in the complex, although it has low or no detectable affinity for either component alone [13].
  • Based on these observations, we propose a model for the assembly and architecture of the GDNF-GFR alpha 1-RET complex [13].
  • We report the isolation and characterization of rat and human cDNAs for a novel cell-surface associated accessory protein, RETL2, that shares 49% identity with RETL1 [19].
  • Two additional members of the GFR alpha family of GPI-linked proteins have recently been cloned: GFR alpha-3 and GFR alpha-4 [20].
  • Furthermore, it was indicated that PAX2, GFRA1, and EMX2 on distal 10q, in which the deletions could affect urinary and/or genital development, were present in two copies in cases 1 through 8 [21].

Analytical, diagnostic and therapeutic context of GFRA1


  1. Human GFRA1: cloning, mapping, genomic structure, and evaluation as a candidate gene for Hirschsprung disease susceptibility. Angrist, M., Jing, S., Bolk, S., Bentley, K., Nallasamy, S., Halushka, M., Fox, G.M., Chakravarti, A. Genomics (1998) [Pubmed]
  2. Glial cell line-derived neurotrophic factor family receptors are abnormally expressed in aganglionic bowel of a subpopulation of patients with Hirschsprung's disease. Lui, V.C., Samy, E.T., Sham, M.H., Mulligan, L.M., Tam, P.K. Lab. Invest. (2002) [Pubmed]
  3. Glial-derived neurotropic factor and RET gene expression in normal human anterior pituitary cell types and in pituitary tumors. Japón, M.A., Urbano, A.G., Sáez, C., Segura, D.I., Cerro, A.L., Diéguez, C., Alvarez, C.V. J. Clin. Endocrinol. Metab. (2002) [Pubmed]
  4. Expression of GDNF receptor (RET and GDNFR-alpha) mRNAs in the spinal cord of patients with amyotrophic lateral sclerosis. Mitsuma, N., Yamamoto, M., Li, M., Ito, Y., Mitsuma, T., Mutoh, T., Takahashi, M., Sobue, G. Brain Res. (1999) [Pubmed]
  5. Expression of the RET receptor tyrosine kinase and GDNFR-alpha in normal and leukemic human hematopoietic cells and stromal cells of the bone marrow microenvironment. Gattei, V., Celetti, A., Cerrato, A., Degan, M., De Iuliis, A., Rossi, F.M., Chiappetta, G., Consales, C., Improta, S., Zagonel, V., Aldinucci, D., Agosti, V., Santoro, M., Vecchio, G., Pinto, A., Grieco, M. Blood (1997) [Pubmed]
  6. Germline mutations of the RET ligand GDNF are not sufficient to cause Hirschsprung disease. Salomon, R., Attié, T., Pelet, A., Bidaud, C., Eng, C., Amiel, J., Sarnacki, S., Goulet, O., Ricour, C., Nihoul-Fékété, C., Munnich, A., Lyonnet, S. Nat. Genet. (1996) [Pubmed]
  7. The tip-top branching ureter. Sariola, H., Sainio, K. Curr. Opin. Cell Biol. (1997) [Pubmed]
  8. Is GAS1 a co-receptor for the GDNF family of ligands? Schueler-Furman, O., Glick, E., Segovia, J., Linial, M. Trends Pharmacol. Sci. (2006) [Pubmed]
  9. A whole-genome scan for 24-hour respiration rate: a major locus at 10q26 influences respiration during sleep. de Geus, E.J., Posthuma, D., Kupper, N., van den Berg, M., Willemsen, G., Beem, A.L., Slagboom, P.E., Boomsma, D.I. Am. J. Hum. Genet. (2005) [Pubmed]
  10. Glial cell line-derived neurotrophic factor and its receptor ret is a novel ligand-receptor complex critical for survival response during podocyte injury. Tsui, C.C., Shankland, S.J., Pierchala, B.A. J. Am. Soc. Nephrol. (2006) [Pubmed]
  11. The role of glial cell line-derived neurotrophic factor (GDNF) and integrins for invasion and metastasis in human pancreatic cancer cells. Funahashi, H., Okada, Y., Sawai, H., Takahashi, H., Matsuo, Y., Takeyama, H., Manabe, T. Journal of surgical oncology. (2005) [Pubmed]
  12. Glial cell line-derived neurotrophic factor/neurturin-induced differentiation and its enhancement by retinoic acid in primary human neuroblastomas expressing c-Ret, GFR alpha-1, and GFR alpha-2. Hishiki, T., Nimura, Y., Isogai, E., Kondo, K., Ichimiya, S., Nakamura, Y., Ozaki, T., Sakiyama, S., Hirose, M., Seki, N., Takahashi, H., Ohnuma, N., Tanabe, M., Nakagawara, A. Cancer Res. (1998) [Pubmed]
  13. Identification of a surface for binding to the GDNF-GFR alpha 1 complex in the first cadherin-like domain of RET. Kjaer, S., Ibáñez, C.F. J. Biol. Chem. (2003) [Pubmed]
  14. Full activation of MEN2B mutant RET by an additional MEN2A mutation or by ligand GDNF stimulation. Bongarzone, I., Vigano, E., Alberti, L., Borrello, M.G., Pasini, B., Greco, A., Mondellini, P., Smith, D.P., Ponder, B.A., Romeo, G., Pierotti, M.A. Oncogene (1998) [Pubmed]
  15. GDNF - a stranger in the TGF-beta superfamily? Saarma, M. Eur. J. Biochem. (2000) [Pubmed]
  16. Roles for GFRalpha1 receptors in zebrafish enteric nervous system development. Shepherd, I.T., Pietsch, J., Elworthy, S., Kelsh, R.N., Raible, D.W. Development (2004) [Pubmed]
  17. De novo mutation of GDNF, ligand for the RET/GDNFR-alpha receptor complex, in Hirschsprung disease. Ivanchuk, S.M., Myers, S.M., Eng, C., Mulligan, L.M. Hum. Mol. Genet. (1996) [Pubmed]
  18. Glial cell line-derived neurotrophic factor differentially stimulates ret mutants associated with the multiple endocrine neoplasia type 2 syndromes and Hirschsprung's disease. Carlomagno, F., Melillo, R.M., Visconti, R., Salvatore, G., De Vita, G., Lupoli, G., Yu, Y., Jing, S., Vecchio, G., Fusco, A., Santoro, M. Endocrinology (1998) [Pubmed]
  19. Glial cell line-derived neurotrophic factor-dependent RET activation can be mediated by two different cell-surface accessory proteins. Sanicola, M., Hession, C., Worley, D., Carmillo, P., Ehrenfels, C., Walus, L., Robinson, S., Jaworski, G., Wei, H., Tizard, R., Whitty, A., Pepinsky, R.B., Cate, R.L. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  20. GFR alpha-4 and the tyrosine kinase Ret form a functional receptor complex for persephin. Enokido, Y., de Sauvage, F., Hongo, J.A., Ninkina, N., Rosenthal, A., Buchman, V.L., Davies, A.M. Curr. Biol. (1998) [Pubmed]
  21. Genetic evidence for a novel gene(s) involved in urogenital development on 10q26. Ogata, T., Muroya, K., Sasagawa, I., Kosho, T., Wakui, K., Sakazume, S., Ito, K., Matsuo, N., Ohashi, H., Nagai, T. Kidney Int. (2000) [Pubmed]
  22. Genomic structure and chromosomal localization of the human GDNFR-alpha gene. Eng, C., Myers, S.M., Kogon, M.D., Sanicola, M., Hession, C., Cate, R.L., Mulligan, L.M. Oncogene (1998) [Pubmed]
  23. Glial cell-derived neurotrophic factor (GDNF)-induced migration and signal transduction in corneal epithelial cells. You, L., Ebner, S., Kruse, F.E. Invest. Ophthalmol. Vis. Sci. (2001) [Pubmed]
  24. Perturbation of RET signaling in the embryonic kidney. Ehrenfels, C.W., Carmillo, P.J., Orozco, O., Cate, R.L., Sanicola, M. Dev. Genet. (1999) [Pubmed]
  25. Mutational analysis of the GDNF/RET-GDNFR alpha signaling complex in a kindred with vesicoureteral reflux. Shefelbine, S.E., Khorana, S., Schultz, P.N., Huang, E., Thobe, N., Hu, Z.J., Fox, G.M., Jing, S., Cote, G.J., Gagel, R.F. Hum. Genet. (1998) [Pubmed]
  26. Expression of GDNF and GDNFR-alpha mRNAs in muscles of patients with motor neuron diseases. Yamamoto, M., Mitsuma, N., Inukai, A., Ito, Y., Li, M., Mitsuma, T., Sobue, G. Neurochem. Res. (1999) [Pubmed]
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