Alternative titles; symbols
HGNC Approved Gene Symbol: GFRA1
Cytogenetic location: 10q25.3 Genomic coordinates (GRCh38): 10:116,056,925-116,274,705 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q25.3 | Renal hypodysplasia/aplasia 4 | 619887 | Autosomal recessive | 3 |
Glial cell line-derived neurotrophic factor (GDNF; 600837) is a potent neurotrophic factor that affects several types of neurons from both the central and peripheral nervous systems. Jing et al. (1996) reported the expression cloning and characterization of rat Gdnfr-alpha, a glycosylphosphatidylinositol-linked cell surface receptor for Gdnf. They used the rat cDNA to isolate cDNAs corresponding to the human gene, encoding a deduced 465-amino acid polypeptide that shares 93% sequence identity with the rat protein.
Eng et al. (1998) showed that the human GFRA1 gene comprises 9 exons. Shefelbine et al. (1998) demonstrated that the GFRA1 RNA transcript is alternatively processed.
Using fluorescence in situ hybridization, Gorodinsky et al. (1997) and Eng et al. (1998) mapped the GFRA1 gene to 10q26. Shefelbine et al. (1998) mapped GFRA1 to chromosome 10q25-q26 by radiation hybrid mapping. Puliti et al. (1997) mapped the Gfra1 gene to mouse chromosome 19 in a region with known homology to human 10q24-q26. Puliti et al. (1997) commented on the possibility that GFRA1 is a candidate gene for Hirschsprung disease.
Jing et al. (1996) showed that recombinant GDNFR bound GDNF specifically and mediated activation of the RET protein-tyrosine kinase (RET; 164761). They noted that loss-of-function mutations in RET are involved in Hirschsprung disease (142623), which is characterized by the congenital absence of parasympathetic innervation of the lower intestinal tract. Targeted disruption of the Ret protooncogene in mice results in renal agenesis or severe dysgenesis and lack of enteric neurons throughout the digestive tract. This phenotype closely resembles that of Gdnf-knockout mice, suggesting that both RET and GDNF are involved in signal transduction pathways critical to the development of the kidney and the enteric nervous system. Jing et al. (1996) proposed a model for the stepwise formation of GDNF signal-transducing complex, including GDNF, GDNFR-alpha, and the RET protein-tyrosine kinase.
Paratcha et al. (2001) showed that GFRA1 is released by neuronal cells, Schwann cells, and injured sciatic nerve. RET stimulation in trans by soluble or immobilized GFRA1 potentiates downstream signaling, neurite outgrowth, and neuronal survival, and elicits dramatic localized expansions of axons and growth cones. Soluble GFRA1 mediates robust recruitment of RET to lipid rafts via a mechanism requiring the RET tyrosine kinase. Activated RET associates with different adaptor proteins inside and outside lipid rafts. The authors concluded that these results provide an explanation of the tissue distribution of GFRA1, supporting the physiologic importance of RET activation in trans as a mechanism to potentiate and diversify the biologic responses to GDNF (600837).
Using gene expression profiling, Iwashita et al. (2003) determined that genes associated with Hirschsprung disease were highly upregulated in rat gut neural crest stem cells relative to whole-fetus RNA. The genes with highest expression were GDNF, SOX10 (602229), GFRA1, and EDNRB (131244). The highest expression was seen in RET, which was found to be necessary for neural crest stem cell migration in the gut. GDNF promoted the migration of neural crest stem cells in culture but did not affect their survival or proliferation. The observations made by Iwashita et al. (2003) were confirmed by quantitative RT-PCR, flow cytometry, and functional analysis.
In the probands from 2 unrelated consanguineous families with bilateral renal agenesis (RHDA4; 619887), Arora et al. (2021) identified homozygosity for a nonsense mutation (R226X; 601496.0001) and a 1-bp deletion (601496.0002) in the GFRA1 gene, respectively. Sanger sequencing confirmed the mutations and their segregation with disease in the families. The missense mutation was present in 1 of 251,436 alleles in the gnomAD database, whereas the 1-bp deletion was not found in gnomAD.
In 2 Omani sibs with bilateral renal agenesis, Al-Shamsi et al. (2022) identified homozygosity for a nonsense mutation in the GFRA1 gene (G210X; 601496.0003) that segregated with disease in the consanguineous family and was not found in in-house or public variant databases.
The GFR-alpha Nomenclature Committee (1997) proposed names and symbols for the GPI-linked receptors for the GDNF ligand family. GDNF and neurturin (NTN; 602018) play key roles in the control of vertebrate neuron survival and differentiation. Both signal via a multicomponent receptor system formed by a glycosyl-phosphatidylinositol (GPI)-linked ligand binding subunit (the 'alpha' component) and the receptor tyrosine kinase RET as a signaling (i.e., beta) subunit. The first member of this receptor family to be identified was GDNF receptor-alpha, which binds GDNF and mediates binding and activation of RET. The second member was shown to bind NTN and to mediate activation of RET by both NTN and GDNF. One of the designations for this protein was GDNFR-beta (601956). This nomenclature committee proposed use of the abbreviated name 'GFR-alpha-X' (GDNF family receptor alpha-X) where 'X' denotes an arabic numeral to be assigned based on the date of publication of the receptor. For example, GDNFR-alpha would become GFR-alpha-1 (GFRA1) and GDNFR-beta would be symbolized GFRA2.
Enomoto et al. (2004) noted that Gfra1 is more widely expressed than Ret in mouse and that there is evidence for RET-independent GFRA1 signaling, possibly through NCAM (see 116930), or by capturing and concentrating diffusible GDNF family ligands and presenting them in trans to RET-expressing cells to stimulate RET signaling. Enomoto et al. (2004) generated mice specifically lacking Ret-independent Gfra1 expression. These mice showed no deficits in development of enteric neurons, motor neurons, and kidney or in nerve regeneration. Furthermore, they showed no abnormalities in olfactory bulb, which is a putative site of GDNF-GFRA1-NCAM signaling and requires proper NCAM function for formation. Enomoto et al. (2004) concluded that RET-independent GFRA1 signaling plays a minor role in organogenesis and nerve regeneration.
In a male infant from a consanguineous United Arab Emirates family (family 1) who died soon after birth with bilateral renal agenesis (RHDA4; 619887), Arora et al. (2021) identified homozygosity for a c.676C-T transition (c.676C-T, NM_005264.5) in exon 6 of the GFRA1 gene, resulting in an arg226-to-ter (R226X) substitution. Sanger sequencing confirmed the mutation and its presence in heterozygosity in the unaffected first-cousin parents. The variant was found in 1 of 251,436 alleles in the gnomAD database. A female sib had also died in the neonatal period from renal agenesis.
In the proband from a consanguineous family in which 3 sibs had bilateral renal agenesis (RHDA4; 619887), Arora et al. (2021) identified homozygosity for a 1-bp deletion (c.1294delA, NM_005264.5) in exon 11 of the GFRA1 gene, causing a frameshift predicted to result in a premature termination codon (Thr432ProfsTer13). Sanger sequencing confirmed the deletion and its presence in heterozygosity in the unaffected first-cousin parents. The variant was not found in the gnomAD database.
In 2 Omani sibs with bilateral renal agenesis and Potter sequence (RHDA4; 619887) who died shortly after birth, Al-Shamsi et al. (2022) identified homozygosity for a c.628G-T transversion (c.628G-T, NM_005264.8) in the GFRA1 gene, resulting in a gly210-to-ter (G210X) substitution. Sanger sequencing confirmed the mutation and its presence in heterozygosity in the first-cousin parents. The variant was not found in 1,564 in-house population-specific exomes or in public variant databases. Two more affected sibs in this family had bilateral renal agenesis and features of Potter sequence and died shortly after birth.
Al-Shamsi, B., Al-Kasbi, G., Al-Kindi, A., Bruwer, Z., Al-Kharusi, K., Al-Maawali, A. Biallelic loss-of-function variants of GFRA1 cause lethal bilateral renal agenesis. Europ. J. Med. Genet. 65: 104376, 2022. [PubMed: 34737117] [Full Text: https://doi.org/10.1016/j.ejmg.2021.104376]
Arora, V., Khan, S., El-Hattab, A. W., Puri, R. D., Rocha, M. E., Merdzanic, R., Paknia, O., Beetz, C., Rolfs, A., Bertoli-Avella, A. M., Bauer, P., Verma, I. C. Biallelic pathogenic GFRA1 variants cause autosomal recessive bilateral renal agenesis. J. Am. Soc. Nephrol. 32: 223-228, 2021. [PubMed: 33020172] [Full Text: https://doi.org/10.1681/ASN.2020040478]
Eng, C., Myers, S. M., Kogon, M. D., Sanicola, M., Hession, C., Cate, R. L., Mulligan, L. M. Genomic structure and chromosomal localization of the human GDNFR-alpha gene. Oncogene 16: 597-601, 1998. [PubMed: 9482105] [Full Text: https://doi.org/10.1038/sj.onc.1201573]
Enomoto, H., Hughes, I., Golden, J., Baloh, R. H., Yonemura, S., Heuckeroth, R. O., Johnson, E. M., Jr., Milbrandt, J. GFR-alpha-1 expression in cells lacking RET is dispensable for organogenesis and nerve regeneration. Neuron 44: 623-636, 2004. [PubMed: 15541311] [Full Text: https://doi.org/10.1016/j.neuron.2004.10.032]
GFR-alpha Nomenclature Committee. Nomenclature of GPI-linked receptors for the GDNF ligand family. Neuron 19: 485 only, 1997. [PubMed: 9331342] [Full Text: https://doi.org/10.1016/s0896-6273(00)80365-7]
Gorodinsky, A., Zimonjic, D. B., Popescu, N. C., Milbrandt, J. Assignment of the GDNF family receptor alpha-1 (GFRA1) to human chromosome band 10q26 by in situ hybridization. Cytogenet. Cell Genet. 78: 289-290, 1997. [PubMed: 9465905] [Full Text: https://doi.org/10.1159/000134674]
Iwashita, T., Kruger, G. M., Pardal, R., Kiel, M. J., Morrison, S. J. Hirschsprung disease is linked to defects in neural crest stem cell function. Science 301: 972-976, 2003. [PubMed: 12920301] [Full Text: https://doi.org/10.1126/science.1085649]
Jing, S., Wen, D., Yu, Y., Holst, P. L., Luo, Y., Fang, M., Tamir, R., Antonio, L., Hu, Z., Cupples, R., Louis, J.-C., Hu, S., Altrock, B. W., Fox, G. M. GDNF-induced activation of the Ret protein tyrosine kinase is mediated by GDNFR-alpha, a novel receptor for GDNF. Cell 85: 1113-1124, 1996. [PubMed: 8674117] [Full Text: https://doi.org/10.1016/s0092-8674(00)81311-2]
Paratcha, G., Ledda, F., Baars, L., Coulpier, M., Besset, V., Anders, J., Scott, R., Ibanez, C. F. Released GFR-alpha-1 potentiates downstream signaling, neuronal survival, and differentiation via a novel mechanism of recruitment of c-Ret to lipid rafts. Neuron 29: 171-184, 2001. [PubMed: 11182089] [Full Text: https://doi.org/10.1016/s0896-6273(01)00188-x]
Puliti, A., Cinti, R., Seri, M., Ceccherini, I., Romeo, G. Assignment of mouse Gfra1, the homologue of a new human HSCR candidate gene, to the telomeric region of mouse chromosome 19. Cytogenet. Cell Genet. 78: 291-294, 1997. [PubMed: 9465906] [Full Text: https://doi.org/10.1159/000134675]
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. Mutational analysis of the GDNF/RET-GDNFR-alpha signaling complex in a kindred with vesicoureteral reflux. Hum. Genet. 102: 474-478, 1998. [PubMed: 9600247] [Full Text: https://doi.org/10.1007/s004390050724]