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Human Molecular Genetics Pages 2023-2026 © Oxford University Press
De novo mutation of GDNF, ligand for the RET/GDNFR-[alpha] receptor complex, in Hirschsprung disease
Introduction
Results
Discussion
Materials And Methods
   Patients
   DNA analyses
Acknowledgements
Abbreviations
References

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

De novo mutation of GDNF, ligand for the RET/GDNFR- [alpha] receptor complex, in Hirschsprung disease Stacey M. Ivanchuk+, Shirley M. Myers+, Charis Eng1 and Lois M. Mulligan*

Departments of Pathology and Paediatrics, Queen's University, Kingston, ON, K7L 3N6, Canada and 1Division of Cancer Epidemiology and Control, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 0211-56084, USA

Received August 24, 1996; Revised and Accepted September 25, 1996

Hirschsprung disease (HSCR) is a common congenital abnormality characterized by absence of the enteric ganglia in the hind gut. In 10-40% of HSCR cases, mutations of the RET receptor tyrosine kinase have been found. The recent identification of a multimeric RET ligand/receptor complex suggested that mutations of genes encoding other components of this complex might also occur in HSCR. To investigate this role, we examined the gene for glial cell line-derived neurotrophic factor (GDNF), the circulating ligand of the RET receptor complex, for mutations in a panel of sporadic and familial HSCR. We identified GDNF sequence variants in 2/36 HSCR patients. The first of these was a conservative change which did not affect the GDNF protein sequence. The second variant was a de novo missense mutation in a family with no history of HSCR and without mutation of the RET gene. Thus, our data are consistent with a causative role for GDNF mutations in some HSCR cases.

INTRODUCTION

Hirschsprung disease (HSCR) is a congenital abnormality arising from absence of the enteric nerve plexus in all or part of the hind gut. The disease affects approximately 1/5000 neonates and occurs in both sporadic (80-90%) and familial forms (1 ). The genetic origins of the disease are complex and, to date, mutations in three genes have been implicated in its genesis. Of these, inactivating mutations of the RET proto-oncogene are most frequent, occurring in 10-40% of HSCR cases (2 -4 ). Mutations of the endothelin-3 (EDN3) and endothelin-B receptor (EDNRB) genes account for <5% of all HSCR and are frequently associated with pigmentary abnormalities and hearing loss (reviewed in refs 5 -7 ). Thus, other, as yet unidentified genes may also contribute to HSCR.

Recent studies have suggested that the activation of the RET tyrosine kinase receptor may require the formation of a multimeric receptor complex which includes the glial cell line-derived neurotrophic factor (GDNF) and the glycosyl-phosphatidylinositol-linked protein GDNFR-[alpha] (8 ,9 ). GDNF is proposed to act as a ligand for a multi-subunit receptor in which GDNFR-[alpha] provides the ligand-binding and RET provides the signaling components. Functional assays have shown that, in the absence of either GDNF or GDNFR-[alpha], RET signaling is reduced or absent (8 ,9 ) suggesting that inactivation or abrogation of either GDNF or GDNFR-[alpha] might mimic the effect of inactivating RET mutations. Further, several recent studies have shown that mice null for GDNF have a similar phenotype to RET-/- mice which have agenic or dysgenic kidneys and lack enteric ganglia (10 -13 ). Thus, the GDNF and GDNFR-[alpha]genes represent additional targets for mutations contributing to HSCR. To investigate the role of GDNF in HSCR, we screened a panel of unrelated HSCR patients for GDNF mutations by direct genomic sequencing. Our data suggest that mutations in GDNF may also contribute to the genesis of HSCR.

RESULTS

Genomic DNA from 16 sporadic HSCR patients and affected members of 20 HSCR families were analyzed by direct genomic sequencing for mutations of the GDNF coding sequence. Two sequence variants were identified in HSCR patients. The first of these, a G -> A substitution at base pair (bp) 429 in exon 2, was a silent change (R143R) in a patient with HSCR associated with a cytogenetically detectable deletion of chromosome 10q11.2- q21.2 which spanned the RET locus (14 ). The patient had total colonic aganglionosis and some developmental delay but no dysmorphic features. Both parents were healthy and had normal karyotypes, suggesting that the disease phenotype was associated with the deletion on chromosome 10 (14 ). This sequence change was predicted to destroy an RsaI restriction site in the GDNF sequence which was subsequently confirmed in the patient's DNA. The G -> A sequence variant was not detected in 35 other HSCR patients nor in 150 additional control chromosomes (this study, ref. 15 ). However, as this variation does not lead to either amino acid or DNA splicing alterations, it is likely that this change represents an extremely rare DNA sequence polymorphism rather than a disease causing mutation.

The second GDNF sequence variant detected was a missense mutation of codon 154 in exon 2. An A -> T change at bp 460 (Fig. 1 a) resulted in substitution of a serine for the wildtype threonine (T154S) in an individual with sporadic, long segment HSCR (patient HS4-3). This alteration was not detected in 150 normal control chromosomes (this study, ref. 15 ) nor in other members of our HSCR panel. Presence of the mutation was predicted to result in the creation of novel HinfI and HincII restriction sites. To confirm the presence of the mutation in patient HS4-3 and to investigate the parental origin of the mutation, we performed HinfI and HincII digestion of amplified GDNF products from HS4-3 and his parents (family HS4). The novel HinfI and HincII sites were present in DNA from the child but not in that of either parent (Fig. 1 b). Upon interview, no family history of HSCR or related features was elicited. Specifically, there was no evidence of HSCR, constipation, and auditory or pigmentary problems in the proband's parents. Paternity was confirmed using three microsatellite markers (D10S219, D10S1739 and D10S1765) from chromosome 10 (data not shown). Thus, HS4-3 has both a de novo GDNF mutation and a de novo occurrence of HSCR. Further, previous studies did not detect a RET mutation in individual HS4-3. These data may suggest a causative relationship between GDNF genotype and HSCR disease phenotype in this individual.


Figure 1.GDNF mutation in an HSCR patient. (a) Sequence from GDNF exon 2 in patient HS4-3 and a normal control (N). HS4-3 is heterozygous for the normal (ACA) and mutant (TCA) sequence at codon 154. (b) Restriction analysis of GDNF exon 2 PCR products with HinfI and HincII in family HS4. Digestion of the 478 bp product with HinfI produces bands of 363 and 115 bp in the absence of the T154S mutation. In the presence of the mutation, novel bands of 195 and 168 bp are generated by cleavage of the 363 bp fragment. The 478 bp product is not digested by HincII in the absence of the mutation. When T154S is present, novel bands of 303 and 175 bp are generated. M = DNA marker, 100 bp ladder (BRL, Burlington ON).

DISCUSSION

We have identified two sequence variants at the GDNF locus in patients with sporadic HSCR (Fig. 2 ). The first of these, a conservative substitution of G -> A at bp 429 is unlikely to result in an altered GDNF protein. This variant does not, however, represent a common polymorphism as it was not found in 150 normal control chromosomes. Whether the presence of this sequence variant has bearing on the expression or severity of disease phenotype in individuals with RET or other HSCR mutations is unknown.


Figure 2.Schematic representation of GDNF. Positions of the mutation and polymorphism identified in this study are shown. The domains of known functional significance are indicated. SS = potential secretion signal; Pro = propeptide; CS = proteolytic cleavage site; C = conserved cysteine residues.

In the second patient, a missense mutation of codon 154 was observed in a de novo case of HSCR. The significance of the T154S mutation is not clear. Although substitution of one small uncharged polar amino acid for another may not appear significant, the functional domains of GDNF have not yet been explored. The threonine residue at position 154 is conserved in mouse and rat although the following amino acid (Thr155) is not [Fig. 2 (8 ,16 ,17 )]. Further, in a recent study, Salomon et al. (15 ) have reported a mutation of codon 150 in a patient with HSCR. Thus, this region may have important functional significance, perhaps in the formation of the GDNF/GDNFR-[alpha]/RET receptor complex.

Functional analyses in vitro, using RET constructs containing several HSCR-type mutations, have demonstrated that RET mutations found in HSCR patients are inactivating, resulting in RET molecules with altered or absent autophosphorylation capabilities (18 ). This is consistent with the phenotype of RET deficient mice which lack enteric ganglia and have dysgenic or agenic kidneys (10 ). Recent studies have revealed a very similar phenotype in mice null for GDNF (11 -13 ), clearly showing that elimination of any part of the GDNF/RET complex generates a similar developmental phenotype. By inference then, a gene encoding any member of the complex represents a candidate gene for HSCR.

We and others have now demonstrated that GDNF mutations do occur in patients with HSCR but that these events are infrequent. Salomon et al. (15 ) have shown that GDNF mutations may occur in HSCR patients with either RET mutations or with trisomy 21. In one family, they showed that HSCR occurs only in individuals who have a RET mutation and not in those without, but that the disease phenotype can occur irrespective of the GDNF mutation. Thus, their data have suggested that, while RET mutations may cause HSCR in absence of GDNF mutations, events at the GDNF locus are neither necessary nor sufficient for HSCR. In this study, we report on an individual with a de novo GDNF mutation which is associated with occurrence of a de novo case of HSCR. Individual HS4-3 was screened and found negative for mutation of the RET proto-oncogene. Further, he does not have trisomy 21 or other phenotypes (e.g. deafness, pigmentary abnormalities) associated with HSCR which might suggest the involvement of another known HSCR locus. At this point, we cannot exclude the possibility of a coincidental de novo occurrence of both the T154S mutation and the HSCR phenotype. Although this mutation lies in a similar region to mutations identified by Salomon et al. (15 ), it affects a codon which showed no mutations in that series. Thus, it is possible that the T154S mutation has functional significance for GDNF but that the mutations of codons 21, 93 and 150 reported by Salomon et al. (15 ) have no associated phenotype. Confirmation of the significance of this mutation awaits a better understanding of the functional domains of GDNF.

Recent studies have shown that the interaction between RET and GDNF is much more complex than a simple receptor-ligand association. Although the assembly order and number of components required for signaling is not yet defined, it appears that interaction of GDNF dimers with GDNFR-[alpha] dimers or monomers occurs as an initial step followed by interaction of this membrane-linked complex to RET dimers with resultant RET autophosphorylation and downstream signaling (8 ,9 ). Disruption of any of these interactions by mutations in any of these subunits will abrogate RET downstream signaling and may equally contribute to genesis of the HSCR phenotype. Our analyses show that mutations in two of the associated components of the GDNF/GDNFR-[alpha]/RET multimeric complex may lead to HSCR. It remains to be seen whether mutations of GDNFR-[alpha] or other, as yet unrecognized, complex members could account for the considerable percentage of HSCR which has not yet been defined at a molecular level.

MATERIALS AND METHODS

Patients

A panel of HSCR patients comprising 16 sporadic cases and 20 families was analyzed. HSCR was diagnosed based on histological examination of biopsy material. A family history of HSCR was recorded only when multiple confirmed HSCR cases were present. DNA samples were obtained for at least one affected member of each family and, where possible, the patient's parents. Due to the limited samples available, linkage analyses were not performed for these families.

DNA analyses

Genomic sequencing. DNA was extracted from peripheral blood samples using standard protocols. Sequencing analyses were performed on PCR amplified genomic DNA samples. GDNF primers used for amplification were:exon 1GDNF1- 5'-GAAGTTATGGGATGTCGTG-3'GDNR5- 5'-AGTCACTGCTCAGCGCGA-3'exon 2GDNF6- 5'-GCCAGAGGATTATCCTGAT-3'GDNR4- 5'-CAGATACATCCACACCTTTTAGCG-3'.

Genomic DNA (100 ng) was amplified for 40 cycles consisting of 1 min at each of 95oC, 55oC and 72oC using conditions previously described (19 ). The amplified products were purified on 2% low melting temperature agarose and eluted through Wizard PCR Prep columns (Promega, Madison WI). Products were sequenced directly using the [Delta]Taq cycle sequencing kit (Amersham-Life Sciences Inc., Arlington Heights IL) by either incorporation of [[alpha]35S]dATP or using a [[gamma]32P]ATP end-labeled primer.

Additional primers used in sequencing were:

GDNF2- 5'-TCGGAGAGGCCAGAGGGGC-3'

GDNR3- 5'-CATCGCAAGAGCCGCTGCAG-3'Restriction digestion. The T154S mutation and R143R polymorphism were confirmed by restriction digestion. Genomic DNA was amplified using primers GDNF6/R4 and purified as described above. Products were digested either with RsaI (R143R) or with HinfI or HincII (T154S) according to manufacturers specifications (BRL, Burlington ON) and resolved on 2% agarose gels.

ACKNOWLEDGEMENTS

We gratefully acknowledge the patients and families, their clinicians and geneticists who participated in this study. We thank L. Fraser, and Drs H. Feilotter and D. Marsh for helpful discussion. This work was supported by grants from the Medical Research Council of Canada (LMM), the Kingston General Hospital and Hospital for Sick Children Foundations (LMM), the Clare Nelson Bequest (LMM), a Lawrence and Susan Marx Investigatorship in Human Cancer Genetics (CE), the Markey Charitable Trust (CE), and the Charles A. Dana Foundation (CE).

ABBREVIATIONS

GDNF, glial cell line-derived neurotrophic factor; GDNFR-[alpha], glial cell line-derived neurotrophic factor receptor [alpha]; HSCR, Hirschsprung disease.

REFERENCES

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8 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. and Fox, G. M. (1996) GDNF-induced activation of the Ret protein tyrosine kinase is mediated by GDNFR-[alpha], a novel receptor for GDNF. Cell, 85,1113-1124. MEDLINE Abstract

9 Treanor, J. J. S., Goodman, L., de Sauvage, F., Stone, D. M., Poulsen, K. T., Beck, C. D., Gray, C., Armanini, M. P., Pollock, R. A., Hefti, F., Phillips, H. S., Goddard, A., Moore, M. W., Buj-Bello, A., Davies, A. M., Asai, N., Takahashi, M., Vandlen, R., Henderson, C. E. and Rosenthal, A. (1996) Characterization of a multicomponent receptor for GDNF. Nature, 382,80-83.

10 Schuchardt, A., D'Agati, V., Larsson-Blomberg, L., Costantini, F. and Pachnis, V. (1994) Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature, 367, 380-383. MEDLINE Abstract

11 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., Sariola, H. and Westphal, H. (1996) Defects in enteric innervation and kidney development in mice lacking GDNF. Nature, 382,73-76. MEDLINE Abstract

12 Moore, M. W., Klein, R. D., Farinas, I., Sauer, H., Armanini, M., Phillips, H., Reichardt, L. F., Ryan, A. M., Carver-Moore, K. and Rosenthal, A. (1996) Renal and neuronal abnormalities in mice lacking GDNF. Nature, 382,76-79. MEDLINE Abstract

13 Sánchez, M.P., Silos-Santiago, I., Frisén, J., He, B., Lira, S.A. and Barbacid, M. (1996) Renal agenesis and the absence of enteric neurons in mice lacking GDNF. Nature, 382,70-73. MEDLINE Abstract

14 Fewtrell, M. S., Tam, P. K. H., Thomson, A. H., Fitchett, M., Currie, J., Huson, S. M. and Mulligan, L. M. (1994) Hirschsprung's disease associated with a deletion of chromosome 10(q11.2q21.2): a further link with the neurocristopathies? J. Med. Genet., 31, 325-327.

15 Salomon, R., Attié, T., Pelet, A., Bidaud, C., Eng, C., Amiel, J., Sarnacki, S., Goulet, O., Ricour, C., Nihoul-Fékété, C., Munnich, A. and Lyonnet, S. (1996) Germline mutations of the RET ligand, GDNF, are not sufficient to cause Hirschsprung disease. Nature Genet., (in press).

16 Hellmich, H.L., Kos, L., Cho, E.S., Mahon, K.A. and Zimmer, A. (1996) Embryonic expression of glial cell-line derived neurotrophic factor (GDNF) suggests multiple developmental roles in neural differentiation and epithelial-mesenchymal interactions. Mech. Dev., 54,95-105. MEDLINE Abstract

17 Lin, L.-F.H., Doherty, D.H., Lile, J.D., Bektesh, S. and Collins, F. (1993) GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science, 260, 1130-1132. MEDLINE Abstract

18 Pasini, B., Borrello, M. G., Greco, A., Bongarzone, I., Luo, Y., Mondellini, P., Alberti, L., Miranda, C., Arighi, E., Bocciardi, R., Seri, M., Barone, V., Radice, M. T., Romeo, G. and Pierotti, M. A. (1995) Loss of function effect of RET mutations causing Hirschsprung disease. Nature Genet., 10, 35-40. MEDLINE Abstract

19 Mulligan, L. M., Eng, C., Healey, C. S., Clayton, D., Kwok, J. B. J., Gardner, E., Ponder, M. A., Frilling, A., Jackson, C. E., Lehnert, H., Neumann, H. P. H., Thibodeau, S. N. and Ponder, B. A. J. (1994) Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nature Genet., 6,70-74. MEDLINE Abstract

*To whom correspondence should be addressed+These authors contributed equally to this work

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