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Original Studies |
Clinical diagnosis group: B. Skogseid, A. Beckers, C. Phelan, M. Edwards, M. Epstein, F. Alford, D. Hurley, S. Grimmond, G. Silins, M. Walters, C. Stewart, J. Cardinal, S. Khodaei, F. Parente, L. Tranebjærg, R. Jorde, J. Menon, A. Khir, T. T. Tan, S. P. Chan, A. Zaini, B. A. K. Khalid, K. Sandelin, N. Thompson, M.-L. Brandi, M. Warth, J. Stock, J. Leisti, D. Cameron, J. J. Shepherd, K. Öberg, M. Nordenskjöld and P. Salmela
Endocrine Tumor (B.T.T., S.Ky., F.F., F.K.W., C.L., C.P.) and Clinical Genetics Units (G.W., S.Kh., P.F., and M.N.), Department of Molecular Medicine, Karolinska Hospital, Sweden; Departments of Clinical Genetics (S.Ky., J.L.) and Internal Medicine (P.S.), Oulu University Hospital, Finland; Queensland Institute of Medical Research (L.B., N.H., G.S., M.W., C.S.), Princess Alexandra Hospital (J.C., D.C.), Hunter Area Health Service (M.Ed.); Princeton Medical Centre Hamilton (M.Ep.); Royal Perth Hospital (D.H.); St. Vincents Hospital (F.A.); Royal Hobart Hospital (J.J.S.), Australia; Department of Internal Medicine, Uppsala University Hospital, Sweden (B.S., K.Ö.); Department of Endocrinology, Sart Tilman University Hopital, Liège, Belgium (A.B.); Departments of Medical Genetics (L.T.) and Internal Medicine (R.J.), University Hospital of Tromsø, Norway; Department of Medicine (J.M.), Queen Elisabeth Hospital, Kuta Kinabalu, Sabah, Malaysia; Faculty of Medicine, University of Malaya (A.K., S.P.C., A.Z.), University Kebangsaan Malaysia (T.T.T., B.A.K.K) Kuala Lumpur, Malaysia; University of Michigan Hospital (N.T.), Ann Arbor, Michigan; Department of Clinical Physiopathology (M.-L.B.), University of Florence, Italy; Endocrinology, Memorial Hospital (M.W., J.S.), Worcester, Massachussets
Address all correspondence and requests for reprints to: Catharina Larsson, M.D., Ph.D., Endocrine Tumor Unit, Department of Molecular Medicine, Karolinska Hospital CMM L8:01, S-171 76 Stockholm, Sweden. E-mail: Catharina.Larsson{at}cmm.ki.se
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Abstract |
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 Top Abstract IntroductionSubjects, Materials, and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects, Materials, and MethodsResultsDiscussionReferences |
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A number of reported kindreds with familial endocrine disorder, notably familial isolated hyperparathyroidism (FIHP) and familial pituitary tumors, had been considered as variants of MEN 1. Some of these families were found to be linked to the MEN1 locus, while some were excluded. To date, all FIHP families tested genetically were assigned to the loci of either MEN 1 (8) or the hyperparathyroidism-jaw-tumor syndrome (HP-JT), which was mapped to chromosome 1q21-q32 (9, 10). In the case of familial pituitary tumors, the majority of reported families were mainly characterized by familial acromegaly. In these families the mode of transmission was considered as autosomal dominant, and reduced penetrance was frequently found. In addition, the families were usually small compared with those of classical MEN 1, and a number of them also had additional endocrine lesions (11, 12). To date, linkage to MEN1 has been excluded in two kindreds but no new locus has been assigned (11, 12). However, in one Japanese family with 3 affected members, linkage to MEN1 could not be excluded, and loss of heterozygosity of the "wild-type" alleles was found in two tumors from the two brothers (13).
The present mutation screening was undertaken to further elucidate the repertoire of mutations in MEN 1 patients and its possible role in FIHP and familial acromegaly.
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Subjects, Materials, and Methods |
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TopAbstractIntroductionSubjects, Materials, and MethodsResultsDiscussionReferences |
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Informed consent was obtained from all patients, and the study was approved by the local Ethical Committees of each participating hospital. The diagnosis of MEN 1 was based on the finding of neoplasia in 2 or more principal MEN 1-related glands i.e. parathyroid, endocrine pancreas, and anterior pituitary. In familial MEN 1, 1 member fulfilling the criteria for MEN 1 and 1 first degree relative with 1 feature had to be found in a kindred. A de novo germline mutation was considered in an individual with clinical features of MEN 1, who had a negative family history including exclusion of the disease in both parents. We performed mutation analysis on a total of 55 MEN 1 families from 7 countries: 16 Finnish, 19 Swedish, 13 Australian, 2 Malaysian (Chinese/Mongolian descent), 3 North American, 1 Italian, and 1 Iranian. The results from 2 of the families (Swe 1–40 and Swe 1–43) have been published previously (6). In addition, we also studied 13 isolated cases with no family history of MEN 1.
Four FIHP families in which linkage to the MEN1 gene could not be excluded by haplotyping or lod score analysis, were included in the present studies. Clinically, these were families with two or more members with primary hyperparathyroidism: one family with four affected cases including a pair of identical twins, one with three cases, and two with two cases. In all cases, multiglandular disease was found, and familial benign hypocalciuric hypercalcemia was excluded by biochemical screening including urine calcium. Families that were linked to the HPT-JT (HRPT2) locus in 1q (10) were not included in the analysis.
The eight acromegaly families comprised seven acromegaly-only families
and one family with two cases of acromegaly, one primary
hyperparathyroidism, and one prolactinoma (12). One of the
acromegaly-only families was the largest reported family, with five
affected cases (14). Five other families have not been reported: one
with three affected (see Fig. 3
below) and four with two affected
members. Family members from these families had been investigated
vigorously for MEN 1 and, except for growth-hormone secreting pituitary
tumors, no evidence of other endocrinopathies could be found.
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Genomic DNA was extracted from peripheral blood samples using
standard methods. The 9 translated exons of the gene were amplified as
15 different fragments of 200–300 bp each, as previously described
(6). Genomic DNA (50 ng) was amplified using standard PCR conditions in
50 mM KCl, 10 mM Tris-HCl,
pH 9.0, 1.5 mM MgCl2 (Promega,
Madison, WI), 0.2 mM dTTP, dCTP, and dGTP, 0.05
mM dATP, and [
-32P]-dATP (NEN,
Boston, MA) at 1 µCi/reaction and 2 U Taq DNA
polymerase (Promega) in a final volume of 15 µL. Thermocycling
conditions consisted of 30 cycles of 1 min at 94 C, 1 min at 62 C, and
1 min at 72 C, followed by one cycle of 5 min extension at 72 C. The
PCR products were then electrophoresed in 25% MDE (FMC, ME) gels at
room temperature for 12 h at 6–8 W. Gels were dried before
autoradiography was carried out.
Direct DNA sequencing
Three acromegaly families were fully sequenced. The rest were studied by SSCA followed by sequencing of the shifted bands. All SSCA shifted bands were excised from the MDE gel and placed in 50 µL of H2O at 37 C for 1 h. A 5 µL aliquot of this solution was then amplified in a 50 µL reaction with the following components: 50 mM KCl, 10 mM Tris-HCl, pH 9.0, 1.5 mM MgCl2(Promega), 0.2 mM dTTP, dCTP, dGTP, and dATP, and 1.5 U of Taq DNA polymerase (Promega). The purified PCR products were sequenced from both strands. For sequence reactions, one of the PCR primers was biotinylated at the 5' end. Solid phase sequence reactions with 35S'-labeled dATP were performed using Dynabeads (Dynal, Chantilly, VA) and Sequenase (USB, Cleveland, OH) according to the manufacturer’s manuals, followed by Terminal Deoxynucleotidyl Transferase (Boehringer Mannheim, Indianapolis, IN) treatment for 15 minutes with the addition of 0.2 mM dNTP’s. Sequence reactions were then run on 6% denaturing polyacrylamide gels and autoradiographed overnight. Confirmation of mutation was carried out in the families to demonstrate segregation of the mutation with the disease. In cases where the mutation created or eliminated a restriction site, restriction cleavage was carried out in the family members. In the cases where the mutation did not affect a restriction site, the mutation was sequenced in affected and unaffected family members. Missense mutations were sought in 100 unaffected individuals.
Genotyping and linkage analysis. Five polymorphic
microsatellite markers close to and flanking MEN1 were
selected (15): D11S480, PYGM, D11S449, D11S4155, and
D11S913. The members of the Norwegian pedigree were also genotyped with
two additional markers D1S1679 and D18S976 to confirm parenthood. PCR
reactions were performed in a total volume of 10 µL containing
50–100 ng of genomic DNA, 50 mM KCl, 10
mM Tris-HCl (pH 8.3), 1.5
mM MgCl2, 125
µM of each dNTP, 2 pmol of each
oligodeoxynucleotide primer (one of which was end-labeled with
[
32P]-dATP), and 0.2 U DNA polymerase (Dynazyme,
Finnzyme Oy, Finland). Samples were amplified using a hot-start of 5
min at 94 C, followed by 25 cycles of denaturing at 94 C for 30 sec,
annealing at 55 C for 30 sec, and elongation at 72 C for 30 sec, and a
final elongation step at 72 C for 7 min. Polyacrylamide gel
electrophoresis was carried out on the PCR products followed by either
autoradiography or Bio-imaging analysis (Bas 1000, Fuji, Japan).
Haplotypes were then constructed.
Two point lod scores were calculated for the acromegly family of Kadazan origin using LINKAGE package 5.1 (15A ). Using a conservative approach, cases III-1, 2, and 6 were labeled as affected, while all unaffected cases were considered as unknown. Familial acromegaly was modeled as a rare autosomal dominant disease with a reduced penetrance (50%). Allele frequencies were set at equal levels.
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Results |
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TopAbstractIntroductionSubjects, Materials, and MethodsResultsDiscussionReferences |
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and 2)
were identified in 27 MEN 1 families (51%) and 9 isolated cases
(69%). These different mutations consisted of 11 frameshift, 6
nonsense, 2 splicing, 2 missense mutations, and 1 in-frame deletion
(Table 1). Five mutations occured in more
than 1 proband: 359del4 in 5, 738del4 in 2, W341X in 2, 1466del12 in 8,
and 1657insC in 2.
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). This mutation was not
present in either of his parents nor in his sister, who were all normal
on clinical and biochemical examination. Parenthood was confirmed by
typing of 6 microsatellite markers from chromosomes 1, 11, and 18. The
results for the 4 markers in 11q13 are shown in Fig. 3. The
MEN1 mutation was transmitted to 2 of the children,
comfirming that the patient carries a de novo germline
MEN1 mutation. These 2 children are in their teens, and
clinical evidence of primary hyperparathyroidism was subsequently found
in the older sister (III-2 Fig. 3), while the younger sister is still
disease free.
No mutation was identified in any of the four FIHP and eight acromegaly
families. One acromegaly family in which MEN 1 could not be excluded by
haplotyping or linkage analysis is shown in Fig. 4. Maxiumum lod scores of 0.86 at 
=
0.0 were obtained with the markers PYGM and D11S4155. However no
MEN1 mutation was found in this family neither by SSCA
screening or full sequencing.
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Discussion |
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TopAbstractIntroductionSubjects, Materials, and MethodsResultsDiscussionReferences |
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We identified 22 different mutations in 27 MEN 1 families and 9 isolated cases. In agreement with previous reports, the majority of these mutations were frameshift or nonsense, which would eliminate the functions of one copy of the gene. These results, together with the findings of inactivating mutations in endocrine tumors that showed LOH of 11q13 (16, 17), support Knudson’s two-hits mutation theory of a tumor suppressor gene (18). In the future, it will be interesting to see how the function of the gene, which will come to light in due course, fits in with this theory. The present study also extends the spectrum of mutations in the MEN1 gene, which spread across most of the translated exons. This wide spectrum of mutations, together with the vast intra- and interfamilial phenotypic variations, implies difficulties in genotype-phenotype correlation. Recently, we identified a number of families with clusterings of thymic carcinoids, uncommon but malignant tumors of which a quarter were associated with MEN 1 (19, 20). Mutation analysis in these families confirmed different germ-line mutations in different exons of the gene (20). In the study of the kindreds with the prolactinoma variant, which is considered a distinct MEN 1 phenotype MEN1Burin, three different genotypes were found. Two mutations were in different exons and one not detected, thus excluding any genotype-phenotype correlation (7).
Mutations were also found in 9 of 13 isolated cases in which no family
history of MEN 1 could be found. This rate of mutation detection made
mutation analysis of the MEN1 gene worthwhile in isolated
cases. All isolated cases had 2 or more of the MEN 1-related features.
In one case, in which the DNA of both parents were available, we
confirmed that it was a de novo mutation (Fig. 2). In
addition, we also found a common mutation, 359del 4 (GTCT) in 5
probands: 2 Swedish, 1 Australian, and 1 Malaysian family of Chinese
origin, and 1 isolated case from Australia. Except the 2 Swedish
families, which shared the same 11q13 haplotype, the others were found
to have different haplotypes. This mutation was also reported in a
French family (6), suggesting the existence of a mutation "warm
spot". Clinically, there was no salient feature in these families
that distinguished them from other MEN 1 families.
Founder effect is well-known in a number of hereditary diseases found in isolated populations. In the Finnish population, which is only 80–100 generations old, some 30 diseases have been reported to be more prevalent than in other populations (21), and identification of some of these genes has shown the existence of common founders (22). As MEN 1 is not more prevalent in the Finnish population, it is expected that new mutation rate would be similar or close to that of other populations. Here we found 2 novel different mutations in the MEN 1 kindreds: 1466del12 and D418N. At least one or more unknown mutations exist since, in 10 other cases, no mutations were identified. The 1466del12 mutation occured in 6 kindreds that shared a common 11q13 haplotype, thus pointing to a common founder in these families. The 9 familial and 1 isolated MEN 1 cases from Finland in which no mutation was detected do not share one common 11q13 haplotype and thus are not expected to have one founder mutation (23).
In agreement with previous studies (7), we did not find mutation in any of the FIHP families. These families were small or incomplete in sampling, thus haplotyping or lod score analysis were inconclusive. It is more likely that a separate gene, for example the one responsible for HPT-JT (yet to be cloned) was involved. It will be interesting to analyze some of the large FIHP families that were assigned to MEN1 (8).
As in FIHP families, we did not detect any mutation in the acromegaly
families. In one family that had been excluded from MEN1 by
linkage analysis (12), it was not so surprising not to find mutation in
the MEN1 gene. However, one other family, shown in Fig. 4, was possibly linked to MEN1. Two siblings and one cousin
developed acromegaly associated with growth hormone-secreting tumors.
However, none of their parents had any feature of acromegaly, and all
biochemical investigations in them were normal. It is possible that the
mutations in all these families were unique and lay in regulatory or
untranscribed regions of the MEN1 gene. More likely,
different genetic defects other than those of the MEN1 gene
might be responsible. A number of genes including
G-proteins, Rb adenyl cyclase, and
GHRH-receptor have been implicated in the pathogenesis of
pituitary disease (24). It will be interesting to study the roles of
these genes in these families.
In conclusion, germline mutations of the MEN1 gene are responsible for the hereditary state of MEN 1, while a number of them most probably represent de novo mutation patients without a family history of the disease. Further characterization of the MEN1 mutations in parallel with functional studies, would elucidate its role both in physiological and pathological states.\.
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Footnotes |
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Received December 16, 1997.
Revised May 28, 1998.
Accepted June 1, 1998.
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