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. 1999 Mar;36(3):217–220.

Investigation of germline GFRα-1 mutations in Hirschsprung disease

S Myers 1, R Salomon 1, A Goessling 1, A Pelet 1, C Eng 1, A von Deimling 1, S Lyonnet 1, L Mulligan 1
PMCID: PMC1734319  PMID: 10204848

Abstract

Inactivating mutations of the RET proto-oncogene and of one of its soluble ligand molecules, glial cell line derived neurotrophic factor (GDNF), have been found in a subset of patients with Hirschsprung disease (HSCR). However, the majority of HSCR mutations remain unidentified. As normal RET function requires a multicomponent ligand complex for activation, other members of the RET ligand complex are primary candidates for these mutations. We investigated the presence of mutations in another member of the RET signalling complex, GDNF family receptor alpha-1 (GFRα-1), in a panel of 269 independent cases of HSCR. We identified 10 polymorphisms at the GFRα-1 locus. Surprisingly, however, we did not identify any sequence variants in our HSCR population that were not also present in a normal control population. Our data suggest that mutations of the GFRα-1 gene are not a common aetiological event in HSCR.


Keywords: RET; Hirschsprung disease; GFRα-1; GDNF

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Selected References

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  1. Amiel J., Attié T., Jan D., Pelet A., Edery P., Bidaud C., Lacombe D., Tam P., Simeoni J., Flori E. Heterozygous endothelin receptor B (EDNRB) mutations in isolated Hirschsprung disease. Hum Mol Genet. 1996 Mar;5(3):355–357. doi: 10.1093/hmg/5.3.355. [DOI] [PubMed] [Google Scholar]
  2. Angrist M., Bolk S., Halushka M., Lapchak P. A., Chakravarti A. Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient. Nat Genet. 1996 Nov;14(3):341–344. doi: 10.1038/ng1196-341. [DOI] [PubMed] [Google Scholar]
  3. Angrist M., Jing S., Bolk S., Bentley K., Nallasamy S., Halushka M., Fox G. M., Chakravarti A. Human GFRA1: cloning, mapping, genomic structure, and evaluation as a candidate gene for Hirschsprung disease susceptibility. Genomics. 1998 Mar 15;48(3):354–362. doi: 10.1006/geno.1997.5191. [DOI] [PubMed] [Google Scholar]
  4. Attié T., Pelet A., Edery P., Eng C., Mulligan L. M., Amiel J., Boutrand L., Beldjord C., Nihoul-Fékété C., Munnich A. Diversity of RET proto-oncogene mutations in familial and sporadic Hirschsprung disease. Hum Mol Genet. 1995 Aug;4(8):1381–1386. doi: 10.1093/hmg/4.8.1381. [DOI] [PubMed] [Google Scholar]
  5. Avantaggiato V., Dathan N. A., Grieco M., Fabien N., Lazzaro D., Fusco A., Simeone A., Santoro M. Developmental expression of the RET protooncogene. Cell Growth Differ. 1994 Mar;5(3):305–311. [PubMed] [Google Scholar]
  6. Baloh R. H., Tansey M. G., Golden J. P., Creedon D. J., Heuckeroth R. O., Keck C. L., Zimonjic D. B., Popescu N. C., Johnson E. M., Jr, Milbrandt J. TrnR2, a novel receptor that mediates neurturin and GDNF signaling through Ret. Neuron. 1997 May;18(5):793–802. doi: 10.1016/s0896-6273(00)80318-9. [DOI] [PubMed] [Google Scholar]
  7. Carlomagno F., Salvatore G., Cirafici A. M., De Vita G., Melillo R. M., de Franciscis V., Billaud M., Fusco A., Santoro M. The different RET-activating capability of mutations of cysteine 620 or cysteine 634 correlates with the multiple endocrine neoplasia type 2 disease phenotype. Cancer Res. 1997 Feb 1;57(3):391–395. [PubMed] [Google Scholar]
  8. Chakravarti A. Endothelin receptor-mediated signaling in hirschsprung disease. Hum Mol Genet. 1996 Mar;5(3):303–307. [PubMed] [Google Scholar]
  9. 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. 1998 Feb 5;16(5):597–601. doi: 10.1038/sj.onc.1201573. [DOI] [PubMed] [Google Scholar]
  10. Hellmich H. L., Kos L., Cho E. S., Mahon K. A., Zimmer A. Embryonic expression of glial cell-line derived neurotrophic factor (GDNF) suggests multiple developmental roles in neural differentiation and epithelial-mesenchymal interactions. Mech Dev. 1996 Jan;54(1):95–105. doi: 10.1016/0925-4773(95)00464-5. [DOI] [PubMed] [Google Scholar]
  11. Ito S., Iwashita T., Asai N., Murakami H., Iwata Y., Sobue G., Takahashi M. Biological properties of Ret with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma, and Hirschsprung's disease phenotype. Cancer Res. 1997 Jul 15;57(14):2870–2872. [PubMed] [Google Scholar]
  12. Ivanchuk S. M., Myers S. M., Eng C., Mulligan L. M. De novo mutation of GDNF, ligand for the RET/GDNFR-alpha receptor complex, in Hirschsprung disease. Hum Mol Genet. 1996 Dec;5(12):2023–2026. doi: 10.1093/hmg/5.12.2023. [DOI] [PubMed] [Google Scholar]
  13. Jing S., Wen D., Yu Y., Holst P. L., Luo Y., Fang M., Tamir R., Antonio L., Hu Z., Cupples R. GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-alpha, a novel receptor for GDNF. Cell. 1996 Jun 28;85(7):1113–1124. doi: 10.1016/s0092-8674(00)81311-2. [DOI] [PubMed] [Google Scholar]
  14. Jing S., Yu Y., Fang M., Hu Z., Holst P. L., Boone T., Delaney J., Schultz H., Zhou R., Fox G. M. GFRalpha-2 and GFRalpha-3 are two new receptors for ligands of the GDNF family. J Biol Chem. 1997 Dec 26;272(52):33111–33117. doi: 10.1074/jbc.272.52.33111. [DOI] [PubMed] [Google Scholar]
  15. Klein R. D., Sherman D., Ho W. H., Stone D., Bennett G. L., Moffat B., Vandlen R., Simmons L., Gu Q., Hongo J. A. A GPI-linked protein that interacts with Ret to form a candidate neurturin receptor. Nature. 1997 Jun 12;387(6634):717–721. doi: 10.1038/42722. [DOI] [PubMed] [Google Scholar]
  16. Kotzbauer P. T., Lampe P. A., Heuckeroth R. O., Golden J. P., Creedon D. J., Johnson E. M., Jr, Milbrandt J. Neurturin, a relative of glial-cell-line-derived neurotrophic factor. Nature. 1996 Dec 5;384(6608):467–470. doi: 10.1038/384467a0. [DOI] [PubMed] [Google Scholar]
  17. Kusafuka T., Wang Y., Puri P. Novel mutations of the endothelin-B receptor gene in isolated patients with Hirschsprung's disease. Hum Mol Genet. 1996 Mar;5(3):347–349. doi: 10.1093/hmg/5.3.347. [DOI] [PubMed] [Google Scholar]
  18. Lin L. F., Doherty D. H., Lile J. D., Bektesh S., Collins F. GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science. 1993 May 21;260(5111):1130–1132. doi: 10.1126/science.8493557. [DOI] [PubMed] [Google Scholar]
  19. Moore M. W., Klein R. D., Fariñas I., Sauer H., Armanini M., Phillips H., Reichardt L. F., Ryan A. M., Carver-Moore K., Rosenthal A. Renal and neuronal abnormalities in mice lacking GDNF. Nature. 1996 Jul 4;382(6586):76–79. doi: 10.1038/382076a0. [DOI] [PubMed] [Google Scholar]
  20. Pachnis V., Mankoo B., Costantini F. Expression of the c-ret proto-oncogene during mouse embryogenesis. Development. 1993 Dec;119(4):1005–1017. doi: 10.1242/dev.119.4.1005. [DOI] [PubMed] [Google Scholar]
  21. Passarge E. The genetics of Hirschsprung's disease. Evidence for heterogeneous etiology and a study of sixty-three families. N Engl J Med. 1967 Jan 19;276(3):138–143. doi: 10.1056/NEJM196701192760303. [DOI] [PubMed] [Google Scholar]
  22. Pichel J. G., Shen L., Sheng H. Z., Granholm A. C., Drago J., Grinberg A., Lee E. J., Huang S. P., Saarma M., Hoffer B. J. Defects in enteric innervation and kidney development in mice lacking GDNF. Nature. 1996 Jul 4;382(6586):73–76. doi: 10.1038/382073a0. [DOI] [PubMed] [Google Scholar]
  23. Pingault V., Bondurand N., Kuhlbrodt K., Goerich D. E., Préhu M. O., Puliti A., Herbarth B., Hermans-Borgmeyer I., Legius E., Matthijs G. SOX10 mutations in patients with Waardenburg-Hirschsprung disease. Nat Genet. 1998 Feb;18(2):171–173. doi: 10.1038/ng0298-171. [DOI] [PubMed] [Google Scholar]
  24. Salomon R., Attié T., Pelet A., Bidaud C., Eng C., Amiel J., Sarnacki S., Goulet O., Ricour C., Nihoul-Fékété C. Germline mutations of the RET ligand GDNF are not sufficient to cause Hirschsprung disease. Nat Genet. 1996 Nov;14(3):345–347. doi: 10.1038/ng1196-345. [DOI] [PubMed] [Google Scholar]
  25. Sanicola M., Hession C., Worley D., Carmillo P., Ehrenfels C., Walus L., Robinson S., Jaworski G., Wei H., Tizard R. Glial cell line-derived neurotrophic factor-dependent RET activation can be mediated by two different cell-surface accessory proteins. Proc Natl Acad Sci U S A. 1997 Jun 10;94(12):6238–6243. doi: 10.1073/pnas.94.12.6238. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Schuchardt A., D'Agati V., Larsson-Blomberg L., Costantini F., Pachnis V. Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature. 1994 Jan 27;367(6461):380–383. doi: 10.1038/367380a0. [DOI] [PubMed] [Google Scholar]
  27. 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. 1998 Apr;102(4):474–478. doi: 10.1007/s004390050724. [DOI] [PubMed] [Google Scholar]
  28. Suvanto P., Wartiovaara K., Lindahl M., Arumae U., Moshnyakov M., Horelli-Kuitunen N., Airaksinen M. S., Palotie A., Sariola H., Saarma M. Cloning, mRNA distribution and chromosomal localisation of the gene for glial cell line-derived neurotrophic factor receptor beta, a homologue to GDNFR-alpha. Hum Mol Genet. 1997 Aug;6(8):1267–1273. doi: 10.1093/hmg/6.8.1267. [DOI] [PubMed] [Google Scholar]
  29. Sánchez M. P., Silos-Santiago I., Frisén J., He B., Lira S. A., Barbacid M. Renal agenesis and the absence of enteric neurons in mice lacking GDNF. Nature. 1996 Jul 4;382(6586):70–73. doi: 10.1038/382070a0. [DOI] [PubMed] [Google Scholar]
  30. Treanor J. J., Goodman L., de Sauvage F., Stone D. M., Poulsen K. T., Beck C. D., Gray C., Armanini M. P., Pollock R. A., Hefti F. Characterization of a multicomponent receptor for GDNF. Nature. 1996 Jul 4;382(6586):80–83. doi: 10.1038/382080a0. [DOI] [PubMed] [Google Scholar]
  31. Trupp M., Belluardo N., Funakoshi H., Ibáez C. F. Complementary and overlapping expression of glial cell line-derived neurotrophic factor (GDNF), c-ret proto-oncogene, and GDNF receptor-alpha indicates multiple mechanisms of trophic actions in the adult rat CNS. J Neurosci. 1997 May 15;17(10):3554–3567. doi: 10.1523/JNEUROSCI.17-10-03554.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]

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