Disease relevance of GFRA1

• Human GFRA1: cloning, mapping, genomic structure, and evaluation as a candidate gene for Hirschsprung disease susceptibility [1].
• In normal infants and normoganglionic colon of patients with HSCR, the expression of GFRA1 was restricted to the glial cells and neurones of the ganglion plexuses [2].
• Lastly, we found strong positive immunostaining for GFRalpha1 in 90% of the somatotropinomas and 50% of the corticotropinomas as well as in 1 of 8 prolactinomas and 1 of 13 nonfunctioning adenomas [3].
• Expression of GDNF receptor (RET and GDNFR-alpha) mRNAs in the spinal cord of patients with amyotrophic lateral sclerosis [4].
• RET broad detection in primary tumors was not paralleled by the mutual expression of GDNFR-alpha, which was detected only in 2 isolated primary samples and in 3 leukemia/lymphoma cell lines [5].

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

• Ret, the GDNF receptor tyrosine kinase, was upregulated in podocytes in the passive Heymann nephritis and puromycin aminonucleoside (PA) nephrosis rat models of podocyte injury [10].
• CONCLUSION: The enhancement of integrin expression by GDNF signaling through the GDNF receptor strongly influences invasion and adhesion to ECM proteins by pancreatic cancer cells [11].

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

• Hypertrophied nerve fibers were not found to express GFRA1 [2].
• Gfra genes are also expressed in regions of the zebrafish brain and peripheral ganglia, expression domains conserved with other species [16].
• On the other hand, the GDNFR-alpha mRNA levels in the motor neurons were similar in ALS and controls [4].
• Semiquantitative RT-PCR analysis revealed that RET mRNA levels in the ALS spinal cord anterior horn were reduced to one fifth of controls in proportion to motor neuron loss, whereas GDNFR-alpha mRNA was unchanged [4].
• GPI-anchored GFRalpha receptors are localized in plasma membrane to lipid rafts [15].

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

• De novo mutation of GDNF, ligand for the RET/GDNFR-alpha receptor complex, in Hirschsprung disease [17].

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

• In this study, the genomic organization of human GDNFR-alpha was delineated through a combination of PAC clone characterization, long distance PCR and sequence analyses [22].
• METHODS: Expression of GDNF receptor (GFR) alpha-1 in human corneal epithelium was detected by RT-PCR and Western blot analysis [23].
• We have also performed immunohistochemistry with a GFR alpha-1 specific polyclonal antisera to localize GFR alpha-1 protein expression in the developing kidney [24].
• The GDNFR alpha gene was mapped to chromosome 10q25-26 by radiation hybrid techniques and was eliminated as the causative gene by haplotype analysis and sequencing of cDNA from an obligate carrier [25].
• In situ hybridization study revealed that GDNF and GDNFR-alpha mRNAs were localized in subsarcolemmal space of muscle cells [26].

References