ORPHA: 388; MONDO: 0013383;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5p13.2 | {Hirschsprung disease, susceptibility to, 3} | 613711 | Autosomal dominant | 3 | GDNF | 600837 |
A number sign (#) is used with this entry because of evidence that susceptibility to Hirschsprung disease-3 (HSCR3) is associated with variation in the GDNF gene (600837) on chromosome 5p13.
The disorder described by Hirschsprung (1888) and known as Hirschsprung disease or aganglionic megacolon is characterized by congenital absence of intrinsic ganglion cells in the myenteric (Auerbach) and submucosal (Meissner) plexuses of the gastrointestinal tract. Patients are diagnosed with the short-segment form (S-HSCR, approximately 80% of cases) when the aganglionic segment does not extend beyond the upper sigmoid, and with the long-segment form (L-HSCR) when aganglionosis extends proximal to the sigmoid. Total colonic aganglionosis and total intestinal HSCR also occur (Amiel et al., 2008).
Isolated HSCR appears to be of complex nonmendelian inheritance with low sex-dependent penetrance and variable expression according to the length of the aganglionic segment, suggestive of the involvement of one or more genes with low penetrance (Amiel et al., 2008).
Hofstra et al. (1997) discussed the possible role of GDNF in the pathogenesis of Hirschsprung disease.
For a discussion of genetic heterogeneity of susceptibility to Hirschsprung disease, see 142623.
In a patient with Hirschsprung disease with a known RET mutation (164761) and malrotation of the gut, Angrist et al. (1996) identified a mutation in the GDNF gene (600837.0001). The data suggested that RET and GDNF mutations may act in concert to produce an enteric phenotype.
Salomon et al. (1996) analyzed GDNF mutations in 173 Hirschsprung disease patients and concluded that mutations in GDNF per se are neither necessary nor sufficient to cause HSCR, but may influence susceptibility to the disease especially in conjunction with other loci such as RET.
In 1 of 36 patients with HSCR, Ivanchuk et al. (1996) identified a mutation in the GDNF gene (600837.0003). The patient did not have a mutation in the RET gene and there was no family history of the disorder. Ivanchuk et al. (1996) concluded that GDNF mutations may be causative in some cases of HSCR.
Eketjall and Ibanez (2002) characterized the effect of 4 mutations in the rat Gdnf gene on the ability of rat protein to bind and activate its receptors. These mutations corresponded to the substitutions R93W (600837.0001), D150N (600837.0002), T154S (600837.0003), and I211M (600837.0004) in the GDNF gene that were identified in patients with HSCR. Although none of the 4 mutations appeared to affect the ability of Gdnf to activate Ret, D150N and I211M resulted in a significant reduction in the binding affinity of Gdnf for the binding subunit of the receptor complex, Gfra1. Eketjall and Ibanez (2002) hypothesized that although none of the GDNF mutations identified to that time in HSCR patients were sufficient to cause HSCR, some may contribute to pathogenesis of the disorder in conjunction with other genetic lesions.
Borghini et al. (2002) produced 5 GDNF mutant proteins in COS-7 cells and tested their effect on RET-expressing neuroblastoma cells. The degree of RET receptor activation observed was comparable to that induced by the wildtype GDNF protein. This observation was consistent with the lack of a clear genotype-phenotype correlation of GDNF mutations in Hirschsprung disease patients.
Amiel, J., Sproat-Emison, E., Garcia-Barceo, M., Lantieri, F., Burzynski, G., Borrego, S., Pelet, A., Arnold, S., Miao, X., Griseri, P., Brooks, A. S., Antinolo, G., and 12 others. Hirschsprung disease: associated syndromes and genetics: a review. J. Med. Genet. 45: 1-14, 2008. [PubMed: 17965226] [Full Text: https://doi.org/10.1136/jmg.2007.053959]
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. Nature Genet. 14: 341-343, 1996. [PubMed: 8896568] [Full Text: https://doi.org/10.1038/ng1196-341]
Borghini, S., Bocciardi, R., Bonardi, G., Matera, I., Santamaria, G., Ravazzolo, R., Ceccherini, I. Hirschsprung associated GDNF mutations do not prevent RET activation. Europ. J. Hum. Genet. 10: 183-187, 2002. [PubMed: 11973622] [Full Text: https://doi.org/10.1038/sj.ejhg.5200785]
Eketjall, S., Ibanez, C. F. Functional characterization of mutations in the GDNF gene of patients with Hirschsprung disease. Hum. Molec. Genet. 11: 325-329, 2002. [PubMed: 11823451] [Full Text: https://doi.org/10.1093/hmg/11.3.325]
Hirschsprung, H. Stuhltragheit Neugeborener in Folge von Dilatation und Hypertrophie des Colons. Jahrb. Kinderheilk. 27: 1-7, 1888.
Hofstra, R. M. W., Osinga, J., Buys, C. H. C. M. Mutations in Hirschsprung disease: when does a mutation contribute to the phenotype? Europ. J. Hum. Genet. 5: 180-185, 1997. [PubMed: 9359036]
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. Molec. Genet. 5: 2023-2026, 1996. [PubMed: 8968758] [Full Text: https://doi.org/10.1093/hmg/5.12.2023]
Salomon, R., Attie, T., Pelet, A., Bidaud, C., Eng, C., Amiel, J., Sarnacki, S., Goulet, O., Ricour, C., Nihoul-Fekete, C., Munnich, A., Lyonnet, S. Germline mutations of the RET ligand GDNF are not sufficient to cause Hirschsprung disease. Nature Genet. 14: 345-347, 1996. [PubMed: 8896569] [Full Text: https://doi.org/10.1038/ng1196-345]