Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1.
ABSTRACT Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by tumours of the parathyroids, pancreas and anterior pituitary that represents one of the familial cancer syndromes. The MEN1 locus has been previously localised to chromosome 11q13, and a <300 kb gene-rich region flanked centromerically by PYGM and telomerically by D11S1783 defined by combined meiotic and tumour deletion mapping studies. Two candidate genes, ZFM1 and PPP2R5B, from this region have been previously excluded, and in order to identify additional candidate genes we used a BAC to isolate cDNAs from a bovine parathyroid cDNA library by direct selection. One of the novel genes that we identified, SCG2, proved to be identical to the recently published MEN1 gene, which is likely to be a tumour suppressor gene. The SCG2 transcript was 2.9 kb in all tissues with an additional 4.2 kb transcript also being present in the pancreas and thymus. Mutational analysis of SCG2 in 10 unrelated MEN1 families identified one polymorphism and nine different heterozygous mutations (one missense, four non-sense, one insertional and three deletional frameshifts) that segregated with the disease, hence providing an independent confirmation for the identification of the MEN1 gene.
Gut 01/2001; 48(4):536-541. DOI:10.1136/gut.48.4.536 · 13.32 Impact Factor
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ABSTRACT: Multiple endocrine neoplasia 1 (MEN1) is a cancer syndrome resulting from mutations of the MEN1 gene. The syndrome is characterized by neoplasia of the parathyroid and pituitary glands, and malignant tumors of the endocrine pancreas. Other manifestations include benign lipomas, angiofibromas, and carcinoid tumors commonly originating in the colon, thymus, and lung. This is the first report of MEN1 syndrome manifesting as bilateral granulosa cell ovarian tumors, and which is associated with a rare intronic mutation of the MEN1 gene. A 41-year-old woman presented with abdominal pain, increasing abdominal girth, and dysmenorrhea. Ultrasound demonstrated enlarged ovaries and uterine fibroids. After an exploratory laparotomy, she subsequently underwent bilateral salpingo-oophorectomy with hysterectomy where the pathology revealed bilateral cystic granulosa cell tumors of the ovaries. Additional workup including computed tomography imaging discovered a thymic mass, which the pathology showed was malignant, along with a pancreatic mass suspicious for a neuroendocrine tumor. Hyperparathyroidism was also discovered and was found to be secondary to a parathyroid adenoma. Genetic testing revealed an exceedingly rare mutation in the MEN1 gene (c.654 + 1 G>A). Mutations of the menin gene leading to MEN1 syndrome are classically nonsense or missense mutations producing a dysfunctional protein product. Recently, researchers described a novel mutation of MEN1 (c.654 + 1 G>A) in a male proband meeting the criteria for clinical MEN1 syndrome. Functional analysis performed on the stable mutant protein showed selective disruption of the transforming growth factor beta signaling pathway, yet it maintained its wild-type ability to inhibit nuclear factor kappa B and to suppress JunD transcriptional activity. To our knowledge, this is the first report of MEN1 syndrome associated with bilateral granulosa cell malignancy. We postulate that this presentation may be due to the novel menin gene mutation recently described.The Application of Clinical Genetics 01/2015; 8:69-73. DOI:10.2147/TACG.S72223
Article: Familial Somatotropinomas[Show abstract] [Hide abstract]
ABSTRACT: This review describes the clinical and genetic aspects of familial somatotropinomas that occur either as components of the multiple endocrine neoplasia type 1 (MEN-1) syndrome, Carney complex or as isolated familial somatotropinomas. Somatotropinomas in MEN-1 are typically associated with acromegaly, with the primary genetic defect being the inactivation of the MEN-1 gene, located on chromosome 11q13. In contrast, somatotropinomas in Carney complex are associated with gigantism or acromegaly. Although the exact gene responsible for Carney complex remains unknown, the disease exhibits genetic heterogeneity; it is linked in some kindreds to chromosome 2p16 and in others, is mapped to chromosome 17q2. Isolated familial somatotropinomas, like somatotropinomas in Carney complex, are associated with both gigantism and acromegaly. However, evidence is accumulating to suggest that the gene responsible for this disease is located within chromosome 11q13 but is distinct from the MEN-1 gene.The Endocrinologist 01/1999; 9(4):277-285. DOI:10.1097/00019616-199907000-00007 · 0.12 Impact Factor