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Original Studies |
Institute for Hormone and Fertility Research, University of Hamburg (I.B., M.R., W.H.), Hamburg; the Division of Endocrinology, Department of Medicine, University of Essen (B.S.), Essen; Endokrinologische Praxisgemeinschaft (K.F.-R., F.R.), Heidelberg; Klinik und Poliklinik für Nuklearmedizin, University of Rostock (P.G.); Endokrinologische Praxisgemeinschaft (M.G.), Stuttgart; and Medical Department II, Klinikum Groshadern, University of Munich (M.M.R.), Munich, Germany
Address all correspondence and requests for reprints to: Wolfgang Höppner Ph.D., Institute for Hormone and Fertility Research, University of Hamburg, Molecular Diagnostic Group, Grandweg 64, D-22529 Hamburg, Germany. E-mail: hoeppner.wolfgang{at}Leidenberger.de
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Abstract |
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Two different mutations in codon 790 (TTG
TTT, TTGTTC;
Leu790Phe) and one mutation in codon 791 (TATTTT;
Tyr791Phe) created a phenylalanine residue.
We conclude that codons 790 and 791 of the ret protooncogene represent a new hot spot for FMTC/MEN-2A causing mutations. With the discovery of these considerably common mutations in codons 790 and 791 and the identification of some rare mutations, 100% of the German FMTC/MEN-2A families could be characterized by a mutation in the ret protooncogene.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The ret protooncogene encodes a receptor tyrosine kinase
that is involved in the normal development of neural crest cell
lineages (6, 7, 8). Glial cell line-derived neurotropic factor (GDNF), a
member of the transforming growth factor-ß superfamily has been
demonstrated to be the ligand for the c-Ret protein (9). The c-Ret
protein forms a dimer that is associated with the glial cell-derived
neurotropic factor 
receptor (GDNFR-), another membrane-bound
receptor for GDNF (10, 11).
Presymptomatic identification of gene carriers by mutation analysis in the ret protooncogene and the option of prophylactic thyroidectomy have had a great impact on the diagnosis and management of FMTC and MEN-2A patients. In all families with an identified mutation in the ret protooncogene, it is possible today to perform a thyroidectomy before C cell carcinoma occurs. Therefore, genetic screening has become a routine procedure for these patients.
In addition, for patients with (apparently) sporadic MTC, the screening for common mutations in the ret protooncogene is used to exclude the hereditary forms of this tumor. Some patients with apparently sporadic MTC turned out to be index cases of new FMTC/MEN-2A families due to de novo mutations or unknown family history.
Genetic analysis is highly reliable in FMTC and MEN-2A if the specific
mutation in the ret protooncogene of the family is known
(92%). In the remaining 8% of the FMTC and MEN-2A families worldwide,
no mutation has been found to date (3). To answer the question of which
genetic defect causes the disease in these families, other loci in the
ret protooncogene as well as the GDNF gene and the GDNFR-
gene are currently under investigation.
In Germany, among 181 FMTC/MEN-2A families, 8 did not have one of the common mutations in exon 10 or 11 of the ret protooncogene. In the present study we report the results of the molecular analysis of 5 families with an unidentified mutation and 11 patients of 305 with apparently sporadic tumors.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Extraction of genomic DNA and amplification of exons 10, 11, 13, 14, 15, and 16 from the ret protooncogene
Genomic DNA was isolated from peripheral blood lymphocytes using the QIAMP blood kit (Qiagen, Hilden, Germany). PCR amplifications were carried out with the following oligonucleotide primers: exon 10, Ret10F (5'-GCAGCATTGTTGGGGGACA-3') and Ret10R (5'-GTCCCGGCCACCCACT-3'; size of amplified fragment, 140 bp); exon 11, Ret11F (5'-CATGAGGCAGAGCATACGCA-3') and Ret11R (5'-GACAGCAGCACCGAGACGAT-3'; size of amplified fragment, 156 bp); exon 13, Ret 13F (5'-AACTTGGGCAAGGCCATCA-3') and Ret13R (5'-AGAACAGGGCTGTATGGAGC-3'; size of amplified fragment, 108 bp); exon 14, Ret14F (5'-AAGACCCAAGCTGCCTGAC-3') and Ret14F (5'-GCTGGGTGCAGAGCCATAT-3'; size of amplified fragment, 294 bp); exon 15, Ret15F (5'-GTGACCGCTGCCTGGCCATGG-3') and Ret15R (5'-CCTAGGCTTCCCAAGGACTGCCTGC-3'; size of amplified fragment, 349 bp); and exon 16, Ret16F (5'-TAACCTCCACCCCAAGAGAG-3') and Ret16R (5'-AGGGATAGGGCCTGGGCTTC-3'; size of amplified fragment, 192 bp). One hundred nanograms of DNA were amplified in a Perkin-Elmer 9600 thermocycler in a volume of 25 µL containing 1 µmol/L of each oligonucleotide primer, 10 mmol/L Tris-HCl (pH 8.3), 2.5 mmol/L MgCl2, and 1 U Taq polymerase (Roche Molecular Systems, Inc., Brauchburg, NJ). The PCR was started with 1 min of denaturation at 95 C, followed by 35 cycles of 1 min each at 65, 72, and 95 C, and completed with 5 min at 72 C. The amplified DNA was analyzed on a 2% agarose gel and purified with the Qiagen Quickspin kit.
For single strand conformational polymorphism screening (exons 10, 11, 13, 14, and 15), the amplified DNA fragments were denatured in formamide-50 µmol/L ethylenediamine tetraacetate and cooled on ice before loading on the gel. Separation was carried out in a vertical gel electrophoresis apparatus in an MDE-gel (AT Biochem, Malvern, PA) at 4 C (exon 10) and 12% polyacrylamide 0.8% bis acrylamide at 45 C (exon 11), 30 C (exon 13), or room temperature (exons 14 and 15) at 240–300 mV for 10–16 h. DNA bands were visualized by silver staining according to standard procedures.
PCR-amplified DNA was sequenced by direct cycle sequencing using the fluorescent-labeled dideoxy terminators (dRhodamine Terminator Cycle Sequencing Ready Reaction Kit, Applied Biosystems, Foster City, CA) and run on the automated sequencer 377 from Applied Biosystems.
The mutation in codon 918 in exon 16 was detected by digestion with the restriction enzyme fokI as described by Hofstra et al. (13).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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DNA sequencing of exons 10, 11, 13, 14, and 15 and mutation-specific restriction enzyme analysis of the mutation in codon 918 (exon 16 of the ret protooncogene) were employed to try to identify mutations in the remaining eight families.
The pedigree of a family with features of multiple endocrine neoplasia
2A, but no mutations in exon 10 or 11 of the ret
protooncogene, is shown in Fig. 1
(pedigree A). The index patient of this family presented with pheo
diagnosed at the age of 31 yr. Elevated serum calcitonin levels were
detected 10 yr later, with subsequent thyroidectomy and histological
diagnosis of MTC. Upon family screening, three members were identified
as having pheo and MTC, and two other members had MTC. Mutation
screening in exons 10 and 11 revealed no mutation. However, sequencing
of exon 13 demonstrated a heterozygous mutation in codon 790
(TTGTTT) converting a leucine to phenylalanine (Fig. 2A). In this family, seven members
carried the mutation (Leu790Phe), and five of them were
clinically affected. The unaffected gene carriers are 26 and 58 yr of
age. One member of this family, who does not carry this mutation, was
biochemically and clinically screened for symptoms of C cell
hyperplasia and pheo with a negative outcome.
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) with three cases of MTC, DNA
analysis revealed no mutation in exon 10 or 11. In this family the same
heterozygous mutation in codon 790 was detected by DNA sequencing
(TTGTTC, LeuPhe), converting leucine to phenylalanine. All three
affected members carry this mutation, whereas three relatives without
this mutation did not display any clinical or biochemical features of
MEN-2A.
Three other pedigrees demonstrating MTC and more than one gene carrier
are shown in Fig. 1 (pedigrees C–E). In pedigree C (Fig. 1), the
heterozygous mutation TTGTTT (LeuPhe) in codon 790 of the
ret protooncogene was detected. For the index patient, MTC
was diagnosed at an age of 46 yr. The 71-yr-old mother of the index
patient is a gene carrier, but showed no clinically symptoms of C cell
hyperplasia, medullary thyroid carcinoma, or pheo. After it was
discovered that she carried the mutation, a normal serum calcitonin was
measured (2 pg/mL).
In pedigree D (Fig. 1) sequencing of exon 13 of the ret
protooncogene revealed a mutation in codon 791 (TATTTT, TyrPhe)
in four of five family members over two generations. One member has a
clinically established MTC, and three gene carriers showed no symptoms
of the MEN-2A syndrome (20, 31, and 43 yr of age).
In pedigree E (Fig. 1), MTC was diagnosed in one member at an age of 21
yr; he was subsequently cured by thyroidectomy. His father had died
from MTC at the age of 45 yr. Mutation analysis revealed the mutation
TATTTT (TyrPhe) in codon 791, exon 13 of the ret
protooncogene of the index patient and his 4-yr-old son.
None of the gene carriers from the above-described families had biochemical evidence of parathyroid disease.
From the remaining three families reported to the German MTC registry with unidentified mutations in the ret protooncogene, one family had a heterozygous mutation in codon 768 in exon 13, a mutation previously described by others (13). In the second of the remaining families, we found a heterozygous mutation in codon 844, exon 14 of the ret protooncogene. For the last family a heterozygous mutation in codon 631 of exon 11 was identified. This mutation is a noncysteine mutation in the vicinity of two cysteines (630 and 634) in the conserved cysteine-rich domain of the Ret protein. Family screening is in progress.
Once our attention had been focussed on the mutations in exon 13, we also screened the sporadic cases of MTC for these mutations. Of 305 patients with apparently sporadic MTC, we discovered 24 patients (8%) with the rare mutations in exons 10 and 11 of the ret protooncogene and 11 (3.7%) additional patients with a mutation in exon 790 or 791 in exon 13 of the ret protooncogene.
The age at diagnosis ranged from 21–64 yr. Upon family screening, in three of these cases additional gene carriers were identified (families F-H). For the remaining eight families, screening is in progress. The index patient of family G presented with pheo and elevated calcitonin levels after pentagastrin stimulation. Histological examination after thyroidectomy revealed Hashimoto’s thyroiditis and struma multinodosa, but no C cell carcinoma. C Cell hyperplasia cannot be ruled out by histological methods, as it is difficult to diagnose in Hashimoto’s thyroiditis and struma multinodosa. The mutation analysis revealed a heterozygous germ-line mutation in codon 791.
To ensure that no other relevant mutations have been overlooked, we screened exons 14 and 15 as well as the MEN-2B-causing mutation in codon 918 of the ret protooncogene. No mutations were detectable in these exons beyond those mentioned above.
To verify that the mutations in codon 790 and 791 of the ret protooncogene are pathogenic mutations, we screened 200 healthy probands (blood donors from a local blood bank). The mutations were not detected in this group. Also, those members without the mutation are clinically unaffected in families with mutations in codon 790/791 of the ret protooncogene, which leads us to the conclusion that it is not a common variant of the ret protooncogene but, rather, a mutation relevant for the disease of these patients.
With the discovery of this new mutational hot spot and some rare noncysteine mutations in exons 11 and 14, 100% of the families with FMTC/MEN-2A in the German MTC/MEN-2A registry can be characterized by a mutation in the ret protooncogene. Furthermore, we were able to detect mutations in 11.6% (8% exon 10 and 11; 3.6% exon 13) from a group of 305 MTC or pheo patients who were apparently sporadic cases and could now be classified as hereditary MTC.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In this paper we describe a new hot spot for mutations in the
ret protooncogene, leading to FMTC and pheo. Three different
mutations affect two adjacent codons in exon 13 converting either
leucine 790 or tyrosine 791 to phenylalanine. These mutations have not
yet been reported for FMTC/MEN-2A families in other countries, where
mutation screening for the ret protooncogene is routinely
performed. It may be that these mutations are specific for the German
population, possibly due to a founder effect. Two reasons argue against
this hypothesis. 1) There are three different base exchanges leading to
a phenylalanine codon in either 790 or 791; this means that three
founders have to be postulated. 2) One of the families with this
mutation has immigrated from the former Yugoslavia and has no family
connections to the German population. The fact that the mutations have
not been detected in other countries may reflect differences in
performing mutation screening. Most of the index patients of the
families with mutations in codons 790 and 791 presented initially as
sporadic cases. In Germany, the MEN-2 study group has recommended
mutation screening for all sporadic MTCs. The mutation analysis for
exon 13 is performed by direct sequencing. In other countries, some
groups only test the mutation in codon 768 by SSCP and restriction
digest (18). These discrepancies, however, reflect the necessity of
international guidelines for the diagnostic procedures for MTC and
FMTC/MEN-2 patients as well as a quality assurance program. The
mutations in codons 790 and 791 differ from the common mutations in
exons 10 and 11 of the ret protooncogene, as they affect not
the extracellular domain of the protein but, rather, the intracellular
TK1 domain. The molecular pathological mechanism leading to the
transformation of cells must be different. It is conceivable that the
presence of a phenylalanine in codon 790 or 791 leads to activation of
the receptor protein. According to the results reported by Liu et
al. (19), at least six tyrosine residues are autophosphorylated in
the Ret protein. Phosphorylation of tyrosine 791 could not be
demonstrated, but also could not be excluded. One could speculate that
autophosphorylation of tyrosine 791 is necessary for the appropriate
ligand-dependent activation of the receptor tyrosine kinase.
Phosphorylation of tyrosine 791 may be prevented either by converting
it to phenylalanine or by a structural change due to a mutation of the
neighboring residue (LeuPhe) resulting in constitutive activation or
inappropriate binding to substrates of the intracellular signaling
pathway. Asai et al. reported recently that binding of the
Shc adaptor depends on the autophosphorylated tyrosine 1062 in the Ret
protein harboring MEN-2A or MEN-2B mutations (20). In this case the
transforming activity is lost when tyrosine 1062 is mutated to
phenylalanine. In contrast to these findings, we consider that the
mutation of Tyr791 to Phe is associated with a gain of
transforming activity. Transfection studies of mutated Ret protein have
to be performed to characterize the precise pathological mechanism and
transformational activity conferred by mutations in codons 790 and
791.
The first family discovered with a mutation in exon 13 of the ret protooncogene had several members who were affected either with MTC or with MTC and pheo. In this family the carrier status for the mutation correlated with the clinical symptoms, and no mutations in exon 14, 15, or 16 were present. This is also true for four other small MTC families with a hitherto unidentified mutation in the ret protooncogene. We, therefore, are confident that this mutation causes the disease. This conclusion is further confirmed by the finding that none of these mutations was detectable in a control group of 200 normal probands.
The phenotype of these mutations is variable. In one family, MTC and pheo occur. In one patient of this family, pheo presented as the first manifestation of the syndrome, and two members have both features. Whereas in one family, the only affected member suffers from pheo. In all of the other families and individual patients, only MTC was diagnosed. In none of the patients was parathyroid disease detected. In addition to the different expression of symptoms of MEN-2A, the age of onset can differ remarkably. It ranges from 21–64 yr. Thirteen patients of 23 (56%) developed the first manifestation of the disease between 30–50 yr of age. On the other hand, the oldest gene carrier without clinical or biochemical manifestation is aged 71 yr.
Investigation of apparently sporadic MTC for ret mutations led to the identification of a large number of individuals with germ-line mutations (11.6%). The newly discovered mutations in exon 13 represent one third of these cases (3.6%). Compared to the established FMTC/MEN-2A families, in which exon 13 mutations represent less than 10%, exon 13 mutations are overrepresented in the group of apparently sporadic MTC.
Due to the small number of families with exon 13 mutations and the variable expression, it is not possible to calculate the penetrance of these mutations. A low penetrance could be the reason why most of these cases were initially not recognized as familial forms and why these mutations are overrepresented in apparently sporadic cases.
The frequency of mutations in exon 13 of the ret protooncogene found in German FMTC/MEN-2A makes it necessary to include mutation screening for codons 790 and 791 in exon 13 into the routine protocol for DNA testing. We expect that the mutations described in this paper will cover a significant proportion of the 8% of the FMTC/MEN-2A families with a hitherto unidentified mutation in the ret protooncogene.
Furthermore, we propose DNA testing for all sporadic MTC patients, as in up to 10% of the cases, they will be hereditary. Testing for the mutations in codon 790/791 also needs to be included, as these mutations are even more frequent in this group than in the already known FMTC/MEN-2A families.
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Acknowledgments |
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Footnotes |
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Received August 18, 1997.
Revised October 14, 1997.
Accepted November 21, 1997.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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,
a novel receptor for GDNF. Cell. 85:1113–1124.[CrossRef][Medline]
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