Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1 (original) (raw)
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Proceedings of the National Academy of Sciences, 1990
The gene for multiple endocrine neoplasia type 1 (MENi), an inherited predisposition to neuroendocrine neoplasm of the parathyroid glands, the pancreatic islet parenchyma, and the anterior pituitary gland, was recently mapped to chromosome 11q13 based on genetic linkage in families. We now show that the pathogenesis of MEN1associated parathyroid lesions involves unmaking of a recessive mutation at the disease locus and that sporadic primary hyperparathyroidism shares the same mechanisms. By examination of allele losses in MENi-associated lesions, we could define deletions of chromosome 11 and map the MEN) locus to a small region within chromosome band 11q13, telomeric to the PYGM locus. In contrast, a low incidence of deletions involving the MEN) gene was found in sporadic pituitary adenomas.
Cancer research, 1997
Multiple endocrine neoplasia type I (MEN!) is an inherited syndrome that results in parathyroid, anterior pituitary, and pancreatic and duode usi endocrine tumors as well as foregut carcinoids in affected patients. The gene responsible for the disease has been linked to chromosome 11q13. We analyzed loss of heterozygosity (LOH) in !88 tumors from 8! patients in an attempt to further define the location of the MENJ gene. Both tumors from MEN! patients and corresponding sporadic tumors were analyzed. Tumor types included parathyroid, gastrinoma, pancreatic endocrine, pituitary, and lung carcinoid. Six tumors (three MEN! and three sporadic tumors) were identified that provided important LOH boundaries. Four tumors (two parathyroid tumors, one gastrinoma, and one lung carcinoid tumor) showed allelic loss that placed the MEN! gene distal to marker PYGM. Two tumors (one gastrinoma and one parathy roid tumor) showed an LOH boundary that placed the gene proximal to D11S449, one of which further moved the telomeric boundary to D11S4936. Taken together, the present data suggest that the MENJ gene lies between PYGM and D11S4936, a region of approximately 300 kb on chromosome llq!3.
Genomics, 1996
tight linkage of the MEN1 locus to the human muscle Linkage analysis and loss of heterozygosity studies glycogen phosphorylase gene (PYGM) at 11q13. Also have shown that the gene responsible for the multiple using linkage analysis, Fujimori et al. (1992) placed the endocrine neoplasia type-1 (MEN1) syndrome localizes MEN1 gene between D11S469 and D11S460, markers to a small interval between D11S427 and D11S460 on centromeric to PYGM and D11S146, respectively. In a chromosome 11q13. As an initial step to clone this turecent linkage analysis, Smith et al. (1995) determined mor suppressor gene, our group is the first to map the that the MEN1 candidate region was flanked by mark-MEN1 region physically using yeast artificial chromoers D11S480 and GSTP1. However, this analysis does some, bacterial artificial chromosome (BAC), and cosnot narrow the region from previous linkage analysis mid contigs. The 1.5-Mb high-resolution, contiguous reports. map extends from PYGM to 300 kb telomeric of Although no homozygous deletions have been re-D11S460. Of this, the 1.2-Mb interval between PYGM ported in MEN1 or related sporadic endocrine tumors, and D11S460 is isolated in cosmids and BACs and will various LOH analyses of tumors have helped to delinbe useful for the development of genomic sequences eate the MEN1 locus. LOH studies by Bystrom et al. and transcription maps of this important region. Nine (1990) localized the MEN1 gene between the markers new sequence-tagged sites (STS) are also characterized from this region. The physical map and the STSs PYGM and D11S146. Similarly, studies performed in will be valuable tools for the cloning of the MEN1 gene. our laboratory demonstrated that the deleted region
Fine-scale mapping of the gene responsible for multiple endocrine neoplasia type 1 (MEN 1)
American journal of human genetics, 1992
We have constructed a high-resolution genetic linkage map in the vicinity of the gene responsible for multiple endocrine neoplasia type 1 (MEN1). The mutation causing this disease, inherited as an autosomal dominant, predisposes carriers to development of neoplastic tumors in the parathyroid, the endocrine pancreas, and the anterior lobe of the pituitary. The 12 markers on the genetic linkage map reported here span nearly 20 cM, and linkage analysis of MEN1 pedigrees has placed the MEN1 locus within the 8-cM region between D11S480 and D11S546. The markers on this map will be useful for prenatal or presymptomatic diagnosis of individuals in families that segregate a mutant allele of the MEN1 gene.
MEN1 gene mutations in 12 MEN1 families and their associated tumors
European Journal of Endocrinology, 1998
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant inherited tumor syndrome characterized by the development of multiple endocrine tumors. The gene responsible for the disease, termed MEN1 gene, has recently been isolated and germline mutations have been described in affected MEN1 individuals. Twelve unrelated German MEN1 families and their associated tumors (5 parathyroid tumors, 1 vipoma, 1 gastrinoma, 1 insulinoma) were characterized for MEN1 gene mutations by single-strand conformational variant (SSCV) analysis and DNA sequence analysis as well as for loss of heterozygosity on chromosome 11q13. We identified nine different heterozygous germline mutations (6 frameshift, 2 missense, 1 nonsense), eight of them were novel. Four of five informative MEN1-associated tumors revealed deletion of the second MEN1 allele, supporting the concept of a tumor suppressor gene. Furthermore, SSCV analysis proved an effective and sensitive method for the detection of menin mutations providing a reliable genetic screening approach supporting genetic counseling and clinical management of MEN1 family members.
Biochemical and Molecular Medicine, 1997
defect had been assigned to chromosome 11q13. inherited as an autosomal dominant disorder, char-Elimination of the wild-type allele at 11q13 loci in acterized by neoplasia and hyperplasia in specific MEN 1 tumors suggests inactivation of a tumor supendocrine organs. The MEN 1 gene, which is most pressor gene in this region as the causative mechaprobably a tumor suppressor gene, has been localnism in MEN 1 tumorigenesis (2). ized to a region of approximately 900 kb on chromosome 11q13. The nuclear factor-kB (NF-kB) is a tran-Loss of heterozygosity studies revealed a smallest scription factor with pleiotropic expression, which region of overlapping deletions in MEN 1-associated is involved in the regulation of expression of many tumors, flanked by the loci D11S427 and D11S97 cellular genes. The p50/p65 heterodimer is the most (3). Previous linkage analysis showed meiotic recomabundant form of NF-kB. The gene encoding the p65 binants in MEN 1 families for the locus D11S807 subunit (NF-kB3/REL A) was recently localized in (4). These studies place the MEN 1 locus between the 900-kb MEN 1 region and was considered a good the centromeric marker D11S427 and the telomeric candidate gene for MEN 1. The structure and nuclemarker D11S807, a region of at most 900 kb (3). otide sequence of the NF-kB3 coding region in MEN Nuclear factor-kB (NF-kB) represents a family of 1 patients were compared with those of non-MEN 1
Human Molecular Genetics, 1997
is an autosomal dominant trait characterized by tumors of the parathyroids, gastro-intestinal endocrine tissue, anterior pituitary and other tissues. We recently cloned the MEN1 gene and confirmed its identity by finding mutations in FMEN1. We have now extended our mutation analysis to 34 more unrelated FMEN1 probands and to two related states, sporadic MEN1 and familial hyperparathyroidism. There was a high prevalence of heterozygous germline MEN1 mutations in sporadic MEN1 (8/11 cases) and in FMEN1 (47/50 probands). One case of sporadic MEN1 was proven to be a new MEN1 mutation. Eight different mutations were observed more than once in FMEN1. Forty different mutations (32 FMEN1 and eight sporadic MEN1) were distributed across the MEN1 gene. Most predicted loss of function of the encoded menin protein, supporting the prediction that MEN1 is a tumor suppressor gene. No MEN1 germline mutation was found in five probands with familial hyperparathyroidism, suggesting that familial hyperparathyroidism often is caused by mutation in another gene or gene(s).
A new mutation of the MEN1 gene in an italian kindred with multiple endocrine neoplasia type 1
European Journal of Endocrinology, 1999
OBJECTIVE: To report a new mutation of the multiple endocrine neoplasia type 1 (MEN1) gene in an Italian kindred. DESIGN: The study included the female proband, aged 50 years, affected by primary hyperparathyroidism, insulinoma and prolactinoma, and ten relatives. Blood samples were obtained for biochemical and genetic analyses. Clinical screening tests included serum glucose, ionized calcium, intact parathyroid hormone, GH, insulin and prolactin. The coding sequence, including nine coding exons and 16 splice sites, was amplified by PCR and directly sequenced. RESULTS: Two additional cases of primary hyperparathyroidism were identified among the paternal family members. The sequence analysis showed a heterozygous T to C transition at codon 444 in exon 9, resulting in a leucine to proline substitution (L444P) in the patient and in the two paternal family members with primary hyperparathyroidism. The L444P amino acid change was absent in 50 normal subjects. The mutation determined the...
Identification of somatic mutations of the MEN1 gene in sporadic endocrine tumours
British journal of …, 2000
Endocrine tumours of the pancreas, anterior pituitary or parathyroids arise either sporadically in the general population, or as a part of inherited syndromes such as multiple endocrine neoplasia type 1 (MEN 1). The mechanisms responsible for the development of sporadic endocrine lesions are not well understood, although loss of heterozygosity (LOH) of the MEN1 locus on chromosome 11q13 and somatic mutation of the MEN1 gene have been frequently associated with the development of MEN 1-type sporadic endocrine lesions. To further investigate the role of the MEN1 gene in sporadic endocrine tumorigenesis, we analysed DNA from 14 primary parathyroid lesions, 8 anterior pituitary tumours and 3 pancreatic tumours for the presence of somatic MEN1 gene mutations and LOH of seven microsatellite markers flanking the MEN1 locus. In addition, we similarly analysed 8 secondary parathyroid lesions which arose in patients with chronic renal failure. None of the patients studied had a family history of MEN 1. Three primary parathyroid lesions and one pancreatic tumour (glucagonoma) were found to have lost one allele at the MEN1 locus. Somatic mutations were identified by SSCP and sequence analysis in one of these parathyroid lesions (P320L) and in the glucagonoma (E179V). These results support previous findings that inactivation of the MEN1 tumour suppressor gene contributes to the development of sporadic MEN 1-type endocrine lesions but is not associated with the development of parathyroid hyperplasia seen in some renal failure patients.