Article Text

Founder effect in multiple endocrine neoplasia type 1 (MEN 1) in Finland

Statistics from Altmetric.com

Editor—Multiple endocrine neoplasia type 1 (MEN 1, OMIM 131100) is transmitted as an autosomal dominant trait with an equal sex distribution and close to full penetrance. Hyperparathyroidism occurs in over 90% of the cases and is invariably associated with multiglandular disease. In addition, the patients may develop tumours of the endocrine pancreas, the anterior pituitary, and the adrenal cortex, as well as lipomas and carcinoids.1The MEN1 tumour suppressor gene at 11q13 was cloned by positional cloning and the protein, menin, has been found to bind specifically to JunD leading to inhibition of JunD activated transcription.2-5 Following the initial description of the disease gene, over 200 MEN1 germline mutations scattered throughout the entire gene have been reported. The majority of these mutations are unique and no clear cut genotype-phenotype correlation has been established so far.3 4 6-13 To date, only a few reports of a founder effect in MEN 1 families have been published.10 14 15 In all the cases, the evidence for a founder chromosome was based on the presence of a shared disease haplotype and aMEN1 mutation, in combination with a common geographical origin of the families involved.

To date, more than 30 rare single gene diseases, mostly autosomal recessive, have been identified in the Finnish population.16 17 The clustering of mutations in the Finnish population can be explained by the mechanisms of isolation, genetic drift, and founder effect. The relatively small founder population, the geographical isolation, and the internal migration movement in the 1500s led to the formation of numerous founder populations. The Finnish population has been widely used in linkage disequilibrium studies for mapping disease gene loci. By combining genetic and clinical investigations with careful genealogical studies, several founder chromosomes for various genetic diseases have been established.17-19

A total of 22 MEN 1 families and four isolated MEN 1 cases have been identified in Finland, 20 of them in the northern part of the country. The diagnosis of MEN 1 was based on the findings of tumours in two or more of the principal MEN 1 related glands (that is, the parathyroid glands, the endocrine pancreas-duodenum, and the anterior pituitary). In familial MEN 1, one or more affected relatives also had clinical, radiological, or surgical evidence of MEN 1 related tumours. Isolated MEN 1 was considered in a subject with clinical features of MEN 1 without a known family history of the disease. Informed consent for the mutation screening and genotyping studies was obtained from the participating patients, and the study was approved by the local ethical committee. Some of the families have been published previously,20 as well as some of the results fromMEN1 mutation screening.9

Mutation analysis on 26 subjects representing each of the 22 familial and four isolated cases was performed using single strand conformation analysis (SSCA) and direct DNA sequencing, as previously described.4 21 For all familial cases where a mutation was detected, its presence in additional family members was tested and confirmed by sequencing or restriction cleavage. Two or more affected members from each of the 22 families were genotyped for five microsatellite markers (D11S1883, D11S4946, D11S4940, D11S4937, and D11S449) spanning the MEN1 region in 11q13. The pedigrees with the two prevailing mutations were further analysed by genealogical studies. The names, dates, and places of birth of ancestors were traced using the Finnish church records, which frequently cover birth and family information back to the years 1650-1700.

The mutation screening of the MEN1 gene showed six different germline mutations in 17 familial (77%) and one isolated (25%) cases. The mutations G42A (GGC→GCC) and 359del4 (GTCT) were located in exon 2, D418N (GAC→AAC) in exon 9, and 1466del12 (GCAGAAGGTGCG), 1657insC, and R527X (CGA→TGA) in exon 10 (fig 1). As expected, most of the mutations were frameshift (359del4, 1657insC), nonsense mutations (R527X), and deletions (1466del12), which are likely to cause truncation of the MEN1gene product, menin, resulting in the loss of its function. The two missense mutations detected, G42A and D418N, are also expected to be pathogenic since they have not been detected in 100 normal subjects. The mutations 1466del12, 1657insC, and R527X were found recurrently in nine, four, and two probands, respectively (fig 1). Four of the mutations identified in this study (359del4, D418N, 1657insC, and R527X) have previously been reported in familial or isolated MEN 1 patients of non-Finnish origin.7-12 14 The regions of the MEN1 gene where these recurrent mutations have occurred consist of CpG, short DNA repeats, or single nucleotide repeat motifs, which have been reported to be prone to mutations in the MEN1 gene.14The codons 83-84, 210-211, and 514-516 appear to be “warm”spots forMEN1 mutations.7 14 The mutations G42A and 1466del12 have not been reported in other populations.

Figure 1

Diagramatic representation of the mutations found in the MEN1 gene in the Finnish population. Each triangle represents one mutation found in one MEN 1 family. Hatched areas are not translated.

MEN1 mutations were not detected in five familial and three isolated cases. In these cases, the mutation could be a large deletion located in regulatory or untranscribed regions of the MEN1 gene, which would be undetectable by the method used. The introns except for the intron/exon boundaries were excluded in the mutation analysis. It has been reported that even 20% of the MEN1 mutations involve intron sequences.12 MEN1 mutations have been found less frequently in isolated than in familial cases, suggesting that some of the isolated cases may have a different genetic aetiology or that two endocrine tumours occur coincidentally in the same patient.6 7 9 10 13

Although the majority of the Finnish population live in the southern part of the country, most of the MEN 1 cases (20/26) were clustered in a limited geographical area in the north of the country. This can be partly explained by clustering of the mutations, a phenomenon, which has been described in many Finnish genetic diseases.16Haplotype analysis showed that the nine families with the 1466del12 mutation shared the same haplotype (6-3-3-7) for the region covered by D11S4946 - D11S4940 - D11S4937 - D11S449 (fig 2). By careful genealogical study, eight families were found to be descended from an identifiable founder couple (fig 2). The couple were born in 1705 and 1709 in a small village where most of the descendants still live. The resulting pedigree consists of eight generations, when counted from the present day patients. It is possible that theMEN1 mutation has occurred beyond the last eight generations, because the connection of the ninth family to this pedigree has not been found even though it shares the same affected haplotype with the other eight families. The mutation analysis showed 1466del12 in the two Finnish families sharing the disease linked haplotype in the previous linkage disequilibrium study.22The age of the 1466del12 mutation and the large family sizes, usually seen in northern Finland, suggest that more mutation carriers than presently known could exist in northern Finland.

Figure 2

Pedigrees of the families with the 1466del12 mutation. Black symbols indicate clinically affected MEN1 mutation carriers. The affected haplotype is outlined by a box. The common ancestor was found for eight of the nine 1466del12 families.

The families with the 1657insC mutation also shared a common haplotype (3-5-3-3-8) with all the five markers (fig 3). Two patients with the same haplotype on both chromosomes do not indicate homozygosity of the mutation, but a common haplotype in the Finnish population. All the four families could be traced back to a couple born in 1844 and 1846, respectively, four generations from the youngest living patients (fig3). Two families sharing the common disease linked haplotype in our previous linkage disequilibrium study22 were found to have the 1657insC mutation.

Figure 3

Pedigrees of the families with the 1657insC mutation. Black symbols indicate clinically affected MEN1 mutation carriers and hatched symbols indicate unaffected (or with unknown clinical status) mutation carriers. The affected haplotype is outlined by a box. The common ancestor was found for all the four families with the 1657insC mutation.

In the two families with the R527X mutation, the disease was clearly linked to different haplotypes, showing that the mutations had occurred independently.

All the 22 families and four isolated cases with MEN 1 fulfilled the criteria for the MEN 1 syndrome with at least two MEN 1 related endocrine organs affected. The main clinical manifestations of the patients with the identified MEN1 mutation are detailed in table 1. In total, 65 affectedMEN1 mutation carriers and 10 clinically unaffected MEN1 mutation carriers were found in these families. Primary hyperparathyroidism (pHPT) was the most common manifestation and was seen in 63 patients (97%). The second most frequent clinical finding was gastroentero-pancreatic tumour (55%), followed by pituitary tumours (28%) and benign adrenal hyperplasia (23%), as well as lipomas (18%) and carcinoids (6%).

Table 1

Clinical manifestations in 18 Finnish MEN1 families with identified MEN1 gene mutation

GEP tumours were more common in the 1466del12 families (68%) than in the 1657insC families (45%), while the occurrence of the pituitary adenomas was the reverse. The differences in the occurrences of the clinical findings might be explained by the varied age and sex of the MEN 1 patients in different families. Families with the prolactinoma variant of MEN 1 families have been reported as a phenotypic variant of MEN 1; however, the mutations were different in these families.6 Several families with isolated hyperparathyroidism have been reported and in some families with at least three affected subjects a mutation of theMEN1 gene (E255K, Q260P, L267P, G305D, Y353X, 1350del3) has been detected.13 21 23-26 pHPT is usually the first symptom of the MEN 1 syndrome and some of the patients in the isolated hyperparathyroidism families may develop MEN 1 syndrome at later ages.

Acknowledgments

The authors wish to thank Mrs Liisa Ukkola and the personnel at the Department of Clinical Genetics in Oulu University Hospital and in other hospitals for collecting blood samples, and the DNA laboratory in Oulu University Hospital for extracting DNA. We are grateful to the clinicians for their help with the collection of clinical data on the patients. This work was supported by grants from the Cancer Society of Northern Finland, the Finnish and Swedish Cancer Foundations, and the Torsten and Ragnar Söderberg Foundations. Soili Kytölä has been a postdoc supported by the Wenner Gren Foundation and by the Karolinska Institutet.

References

View Abstract

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.