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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 9 3361-3364
Copyright © 1998 by The Endocrine Society

Original Studies

Molecular Analysis of the ret and GDNF Genes in a Family with Multiple Endocrine Neoplasia Type 2A and Hirschsprung Disease1

Salud Borrego, Charis Eng2, Beatriz Sánchez, María-Eugenia Sáez, Elena Navarro and Guillermo Antiñolo

Unidad de Genética Médica y Diagnóstico Prenatal (S.B., B.S., M.E.S., G.A.) and Servicio de Endocrinología (E.N.), Hospital Universitario Virgen del Rocío, 41013 Sevilla, Spain; Translational Research Laboratory, Charles A. Dana Human Cancer Genetics Unit, Department of Adult Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115; and Cancer Research Campaign Human Cancer Genetics Research Group, University of Cambridge (C.E.), Cambridge, United Kingdom

Address all correspondence and requests for reprints to: Salud Borrego M.D., Ph.D., Unidad de Genética Médica y Diagnóstico Prenatal, Hospital Universitario Virgen del Rocío, Avenida M.Siurot s/n, 41013 Sevilla, Spain.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The clinical association between multiple endocrine neoplasia type 2 (MEN2) and Hirschsprung disease (HSCR) is infrequent. Germline mutations of the ret protooncogene are the underlying cause of the MEN2 syndromes and a proportion of cases of HSCR. In this report, we describe a new kindred in which the MEN2 and HSCR phenotypes are associated with a single C620S point mutation at one of the cysteine codons of the extracellular domain of the ret protooncogene. We also speculate about the role of a silent mutation in exon 2 of this same gene (A45A), present in a homozygous state in the patient with both MEN2A and HSCR. To investigate the contribution of GDNF to the phenotype observed in this kindred, we scanned the coding region of GDNF in the patient with MEN2/HSCR, but no mutation was found.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
MULTIPLE endocrine neoplasia type 2A (MEN2A) is an inherited cancer syndrome characterized by medullary thyroid carcinoma (MTC) in 95% of the cases, pheochromocytoma in 50% and parathyroid hyperplasia or adenoma in 15–30% of the cases. In 95% of MEN2A families, the affected members have a missense mutation in one of the five cysteine codons of exon 10 (609, 611, 618, and 620) and exon 11 (634) in the ret protooncogene (1). Hirschsprung disease (HSCR) is a genetic disorder characterized by the absence of ganglion cells in the plexuses of the intestinal autonomic nervous system, which affects a variable extent of the intestine, resulting in partial or complete intestinal obstruction during the first years of life. Mutations of the ret protooncogene have been detected in 10–40% of the patients with HSCR, 50% in familial cases and 15–20% in sporadic cases (2, 3, 4).

The ret protooncogene encodes a member of the receptor tyrosine-kinase (RTK) family (5). Activation of the Ret receptor requires the formation of a multimeric receptor complex that includes glial cell line-derived neurotropic factor (GDNF) as ligand and a cell surface-associated accessory protein designated GFR{alpha}-1 (6) (GDNFR-{alpha}, RETL1, or TrnR1) (7, 8). A related ligand, neurturin (NTN), and adaptor molecule GFR{alpha}-2 (RETL2, GDNFR-ß, TrnR2, or NTNR-{alpha}) have been found as well (9, 10, 11, 12, 13). GDNF has been shown to differentially bind GFR{alpha}-1 and GFR{alpha}-2 to mediate Ret activation. Although germline mutations in GDNF have not been identified in MEN2 (14), different studies have identified mutations of GDNF in certain cases of HSCR, although the functional significance of these mutations is not yet clear (15, 16, 17).

Until now, 13 families have been reported in which the MEN2A and HSCR phenotypes are associated with the same ret allele (1, 18, 19, 20, 21, 22). The majority of these families have C618R, C618S, or C620R mutations only. This report describes a new family in which the MEN2A and HSCR phenotypes are associated with C620S, a novel mutation for such families, and with a silent A45A sequence variant in exon 2 of ret.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients

Figure 1Go shows the pedigree of the family. The proband, patient IV-14, required surgery for HSCR at 4 yr of age. At the age of 24 yr, he presented with a thyroid nodule. Family history revealed that his mother (patient III-9) underwent a total thyroidectomy at 46 yr of age, which was apparently diagnosed as papillary thyroid carcinoma. A misdiagnosis was suspected, and a study of calcitonin levels after a pentagastrin stimulation test was performed on patient IV-14. The calcitonin level was 1285 ng/L at 5 min after pentagastrin administration. Catecholamine and metanephrine levels in a 24-h urine collection as well as serum whole calcium and PTH levels were normal. Total thyroidectomy was performed. Bilateral MTC without metastasis to the cervical lymph nodes was verified after histological examination of the resection specimen. Six months postoperatively the levels of calcitonin after a pentagastrin stimulation test remained elevated in patient IV-14. Computed tomography of the neck revealed a 2-cm right paratracheal mass. The patient is currently awaiting surgery. These results prompted rereview of the mother’s thyroidectomy specimen, which was found consistent with the diagnosis of MTC. At this time, her calcitonin level after a pentagastrin stimulation test was elevated. Screening for pheochromocytoma and hyperparathyroidism was negative. The brother of the proband (IV-11) died of complications of HSCR at the age of 8 yr. The clinical examination and biochemical and hormonal studies of the other two siblings of the proband (IV-12 and IV-15) were normal. Patient III-7, maternal uncle of the proband, had an elevated calcitonin levels after pentagastrin stimulation, increased PTH levels, and normal levels of urinary catecholamines and metanephrines. The postsurgical histological study revealed bilateral MTC with thyroglobulin production, cervical lymph node metastasis, and parathyroid hyperplasia. Basal calcitonin levels remained high after surgery. The grandmother of the proband (II-4), who was 78 yr of age, presented with a large goiter, with high basal calcitonin levels, and is awaiting surgery.



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  		Figure 1. Pedigree of the family with MEN2A and HSCR. Individual IV-14 is the proband.

 
Methods

DNA was obtained from white blood cells according to the standard procedure (23). The primers described previously were used for amplification of the 21 exons of ret (18, 24, 25, 26, 27, 28, 29), except those of exon 1 (Men1bF: GTCGCGCCCCCAGTGTCC; Men1bR: ACTGCGCTCCCAGCCGAG) and exon 4 (Men 4b-F: CCCCCTTCCCGAGGAAAG; Men4bR: CGAACTGTGGCCGGAGAC), designed with the PRIME program (GCG Wisconsin Package, Biotechnology Center, Madison, WI).

The search for mutations in exon 10 was performed by fluorescent single strand conformation polymorphism (SSCP). Electrophoresis was performed in an Alf-Express automated DNA sequencer (Pharmacia Biotech, Uppsala, Sweden). The samples that had SSCP variants underwent direct sequencing in the sense and antisense strands by the dideoxynucleotide terminator cycle sequencing method (fmol DNA Sequencing System, Promega, Madison, WI) using primers described previously (27) fluorescently labeled. The gel electrophoresis and analysis were performed in an Alf-Express automated DNA sequencer (Pharmacia Biotech).

The remaining 20 exons were amplified individually and sequenced following the previously described technique or with the ABI Prism Dye Terminator Cycle Sequencing Ready Reaction Kit (Perkin-Elmer, Norwalk, CT) and analyzed in an Applied Biosystems model 373A automated DNA sequencer (Foster City, CA).

GDNF amplification and sequencing were performed according to the protocols described previously (14, 15, 16, 17).

The intragenic ret polymorphisms A45A (exon 2) (27), L769L (exon 13) (27), and S836S (exon 14) (30, 31) were analyzed by restriction of the appropriate PCR amplicons, according to the manufacturer’s instructions.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
PCR-SSCP analysis of exon 10 of ret showed an abnormal band pattern in all of the affected family members, whereas the unaffected members presented a normal band pattern (Fig. 2aGo). Direct sequencing of the amplification product of exon 10 of the affected individuals documented the heterozygous presence of a transversion of a G to a C in the second nucleotide of codon 620 (TGC->TCC). This change produces a missense mutation that results in the substitution of a cysteine residue by serine (C620S; Fig. 2bGo). All individuals with a C620S have MTC. Further, subject III-7 had parathyroid hyperplasia, and subject IV-14 had HSCR.



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  		Figure 2. a, SSCP analysis of exon 10 of the ret protooncogene. Lane 1, Wild-type SSCP pattern in a control individual. Lanes 2–4, No SSCP variants, unaffected individuals of the family (III-11, IV-12, and IV-16, respectively). Lanes 5–8, Affected individuals of the family (II-4, III-7, III-9, and IV-14, respectively) with SSCP band shifts. Lane 9, A nondenatured sample. b, Identification of the C620S mutation by direct sequencing of exon 10 of the ret protooncogene. A, Normal sequence in a control individual. B, Mutated sequence in the affected individual IV-14. The arrow points out a heterozygous transversion of G to C, resulting in a substitution of the amino acid cysteine by serine.

 
To investigate the existence of other alterations in the ret protooncogene besides that identified in exon 10, we analyzed the remaining ret exons and the exon-intron boundaries by sequencing. Three additional variations were detected: one in exon 2 (27), one in exon 13 (27), and one in exon 14 (30, 31). The polymorphisms observed in exons 13 and 14 do not segregate with the disease in this family. On the other hand, it appears that C620S is syntenic to the presence of the A45A polymorphism. Individuals with HSCR and MEN2A or MEN2A only have the C620S-A allele. Of note, the proband is the only family member with both MEN2A and HSCR, the C620S, and the homozygous A/A polymorphism. Analysis of the coding region of the GDNF gene by direct sequencing in patient IV-14 revealed no sequence variants.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this study, we describe a new family with MEN2A and HSCR and a novel ret C620S mutation. All three living affected members have the C620S. Of these, the only affected individual with both MEN2A and HSCR not only carries C620S, but has the homozygous A/A at A45A. Although no firm conclusions can be drawn from this single family, it is tantalizing to speculate that the presence of the homozygous A/A or perhaps the presence of the A in trans from the C620S somehow promotes the expression of both phenotypes in the same individual.

The association of MEN2 and HSCR is infrequent. Until now, there have been described only 13 families in which the MEN2 and HSCR phenotypes are associated with the same ret allele (18, 19, 20, 21, 22).

Recent functional studies (32) show that the cell surface expression of the forms of ret with mutations in codons 609, 618, and 620 is lower than that of ret with a mutation in codon 634. These results suggest that mutations in codons 609, 618, and 620, besides increasing the transforming activity of ret, may interfere with transport of the protein to the plasma membrane. This observation may well explain the coexistence of MEN2 and HSCR due to the exon 10 cysteine codon mutations. The activating cysteine mutations result in MEN2A or familial MTC, whereas the decreased cell surface expression of Ret causes haploinsufficiency and HSCR.

It is possible that a second genetic event occurs to facilitate the coexpression of MEN2 and HSCR phenotypes as well. This genetic event could be the existence of a second ret mutation, a mutation in a modifying gene, or even the presence of an otherwise neutral change in the ret sequence. This second genetic event could modulate the expression of the ret mutation in codon 620 and thus contribute to the susceptibility to HSCR.

As in the MEN2/HSCR families previously reported, we have not found a second pathogenic mutation in the coding region of ret. However, the existence of an apparently harmless variant in ret could modulate the phenotypic expression of the C620S mutation and lead to the MEN2 and HSCR phenotypes. In the analysis of the complete coding sequence of ret in this family, we have detected the presence of three variants that are considered silent polymorphisms. Two of them, one in exon 13 (27) and another in exon 14 (30, 31), do not segregate with the MEN2 and HSCR phenotypes. The polymorphism A45A in exon 2 (27) is present in a heterozygous state in the individuals with MEN2 and in healthy individuals III-10 and IV-12 and is found in a homozygous state (A/A) only in the individual with MEN2 and HSCR. This polymorphism in exon 2 of ret is an apparently silent mutation in the third nucleotide of the alanine codon 45 (GCG->GCA). This polymorphism has been found with HSCR in previous studies (3, 33, 34). It has been shown that the presence of a mutation in the endothelin B receptor gene (EDNRB) and the polymorphism in exon 2 of ret are not randomly associated, and it has been suggested that both genes are required for full penetrance of HSCR (33, 34). In addition, a report by Angrist et al. (3) describes a family in which both siblings affected by HSCR have inherited a missense mutation in exon 2 of ret, namely G93S, from the healthy father and the A45A polymorphism from the mother, who suffers from severe chronic constipation.

As these kinds of sequence variations could lead to an aberrantly spliced product (35), it is necessary to be cautious in the interpretation of apparently neutral variants. The A45A polymorphism found in exon 2 of ret may generate a new acceptor splice site leading to an isoform of messenger ribonucleic acid (mRNA) by alternative splicing. As no fresh tumor or tissue specimen is available, this hypothesis cannot be tested. However, computer-simulated analysis of this possibility predicts that this isoform of mRNA would maintain the published open reading frame (5, 36) and would encode a Ret protein with a 21-amino acid deletion in the extracellular domain (amino acids 25–45), 4 of which correspond to the signal peptide (amino acids 1–28). The functional significance of this mRNA isoform of ret could be a decrease in the expression of the protein on the cell surface. In individuals without any other mutation in ret, this decrease would be compensated by the expression of full-length ret. In individuals homozygous for the polymorphism and with a ret mutation in one of the alleles that decreases protein transport to the plasma membrane, the polymorphism could contribute to the expression of the HSCR phenotype.

The existence of multiple modifying loci outside the 10q11 region is almost certain. The genes that encode the ligands and coreceptors of Ret are excellent candidates. As three independent groups have found germline GDNF mutations in HSCR (15, 16, 17), which may or may not have played modulating roles, we too examined GDNF in this family with both HSCR and MEN2A. However, no variants were noted in this gene in this particular family. Although more molecules are found to be involved in the Ret signaling pathway, whether upstream or downstream, they become prime candidates to play primary or modifying roles in the etiology of HSCR.


   Acknowledgments
 
The authors thank Zimu Zheng for technical assistance. We thank Dr. Galvez for referring the family involved in this study.


   Footnotes
 
1 This work was supported by a grant from the Fondo de Investigaciones Sanitarias (Spain) 98/0898. Back

2 Lawrence and Susan Marx Investigator in Human Cancer Genetics and a Barr Investigator. Back

Received January 16, 1998.

Revised May 13, 1998.

Accepted June 1, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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