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.
- SourceAvailable from: Venkat Dharmarajan
Acute Leukemia - The Scientist's Perspective and Challenge, 12/2011; , ISBN: 978-953-307-553-2
- "Menin functions as a tumor suppressor protein that is mutated in patients with an inherited syndrome called Multiple Endocrine Neoplasia 1 (MEN1) (Chandrasekharappa et al., 1997; Chandrasekharappa and Teh, 2001; Larsson et al., 1988). To date, more than 400 nonsense and frame-shift mutations have been reported in MEN1 patients often developing parathyroid, pancreatic or pituitary tumors after the loss of the wild-type MEN1 allele (Dong et al., 1997; Larsson et al., 1988; Lemmens et al., 1997; Thakker, 2001). Homozygous knockout of MEN1 (-/-) is embryonic lethal in mice, which die at the mid-gestation period with profound defects in liver, heart and the neural tube (Bertolino et al., 2003a; Crabtree et al., 2001; Stewart et al., 1998). "
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- "Menin interacts with the N-terminus of MLL and is required for transformation by MLL fusion proteins (Caslini et al., 2007; Yokoyama et al., 2005). However, MEN1 mutations, which lead to loss of function of the Menin protein, are found in a variety of endocrine tumors including parathyroid hyperplasias and adenomas, as well as pancreatic islet tumor cells establishing Menin as a tumor suppressor (Chandrasekharappa et al., 1997; Lemmens et al., 1997). The similarities in the diseases associated with Menin and PAF subunit mutations (parathyroid and pancreatic islet tumors) raise the possibility that the mechanisms of oncogenicity may also be similar, perhaps mediated through cyclin dependent kinase deregulation as we have previously defined for Menin (Milne et al., 2005b). "
ABSTRACT: MLL is involved in chromosomal rearrangements that generate fusion proteins with deregulated transcriptional activity. The mechanisms of MLL fusion protein-mediated transcriptional activation are poorly understood. Here we show MLL interacts directly with the polymerase associated factor complex (PAFc) through sequences flanking the CxxC domain. PAFc interacts with RNA polymerase II and stimulates posttranslational histone modifications. PAFc augments MLL and MLL-AF9 mediated transcriptional activation of Hoxa9. Conversely, knockdown of PAFc disrupts MLL fusion protein-mediated transcriptional activation and MLL recruitment to target loci. PAFc gene expression is downregulated during hematopoiesis and likely serves to regulate MLL function. Deletions of MLL that abolish interactions with PAFc also eliminate MLL-AF9 mediated immortalization indicating an essential function for this interaction in leukemogenesis.Cancer cell 06/2010; 17(6):609-21. DOI:10.1016/j.ccr.2010.04.012 · 23.89 Impact Factor
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- ", were used as described previously [Pang et al., 1996; Bassett et al., 1998] to determine the haplotypes around the MEN1 locus, which is flanked by the PYGM and D11S1783 loci [Lemmens et al., 1997]. "
ABSTRACT: Phenocopies may confound the clinical diagnoses of hereditary disorders. We report phenocopies in Multiple Endocrine Neoplasia type 1 (MEN1), an autosomal dominant disorder, characterised by the combined occurrence of parathyroid, pituitary and pancreatic tumours. We studied 261 affected individuals from 74 families referred with a clinical diagnosis of MEN1 and sought inconsistencies between the mutational and clinical data. We identified four patients from unrelated families with phenocopies. Patients 1 and 2 from families with MEN1, developed prolactinomas as the sole endocrinopathy but they did not harbour the germline MEN1 mutation present in their affected relatives. Patient 3, had acromegaly and recurrent hypercalcaemia following parathyroidectomy, whilst patient 4 had parathyroid tumours and a microprolactinoma. Patients 3 and 4 and their relatives did not have MEN1 mutations, but instead had familial hypocalciuric hypercalcaemia (FHH) due to a calcium-sensing receptor mutation (p.Arg680Cys), and the hyperparathyroidism-jaw tumour (HPT-JT) syndrome due to a hyperparathyroidism type 2 deletional-frameshift mutation (c.1239delA), respectively. Phenocopies may mimic MEN1 either by occurrence of a single sporadic endocrine tumour in a patient with familial MEN1, or occurrence of two endocrine abnormalities associated with different aetiologies. Phenocopies arose in >5% of MEN1 families, and awareness of them is important in the clinical management of MEN1 and other hereditary disorders.Human Mutation 01/2010; 31(1):E1089-101. DOI:10.1002/humu.21170 · 5.05 Impact Factor