scholarly journals MEN1 syndrome: an anusual case

2015 ◽  
Vol 6 (1S) ◽  
pp. 23-28
Author(s):  
Elena Guidetti ◽  
Monica Cevenini ◽  
Maria Luigia Cipollini ◽  
Martina Ferrata ◽  
Paola Tomassetti ◽  
...  
Keyword(s):  
Multiple Endocrine Neoplasia Type ◽  
Neuroendocrine Tumour ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Men1 Syndrome ◽  
Acid Protein ◽  
Pancreatic Neuroendocrine Tumour ◽  
Inactivating Mutations ◽  
Amino Acid Protein

Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant endocrine disorder and is characterised by the concurrent appearance of adenomas of the parathyroid glands, neuroendocrine-enteropancreatic tumours, and pituitary adenomas, as well as other types of less frequent tumours, such as adrenal cortical tumours, carcinoid tumours, lipomas, etc. Two different forms, familial and sporadic, have been described. The gene responsible, MEN1, consists of 10 exons encoding a 610-amino acid protein known as menin. The MEN1 syndrome is caused by inactivating mutations in MEN1 tumour suppressor gene. The combination of clinical and genetic investigation helps in the diagnosis. Genetic testing has been advocated to identify MEN1 carriers of the MEN1 families for the purpose of earlier detection of tumours. We present a patient with traditionally described manifestations of MEN1 (a parathyroid hyperplasia associated with a pancreatic neuroendocrine tumour and a gastrinoma), but with a negative genetic test for the MEN1 mutation.

scholarly journals Involvement of the MEN1 gene locus in familial isolated hyperparathyroidism

2002 ◽  
pp. 313-322 ◽  
Author(s):  
A Villablanca ◽  
WS Wassif ◽  
T Smith ◽  
A Hoog ◽  
O Vierimaa ◽  
...  
Keyword(s):  
Multiple Endocrine Neoplasia Type ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Comparative Genomic Hybridisation ◽  
Comparative Genomic ◽  
Wild Type ◽  
Chromosome 11 ◽  
Men1 Gene ◽  
Parathyroid Disease

BACKGROUND: Familial isolated hyperparathyroidism (FIHP) is a hereditary disorder characterised by uni- or multiglandular parathyroid disease. A subset of families are likely to be genetic variants of other familial tumour syndromes in which PHPT is the main feature, for example multiple endocrine neoplasia type 1 (MEN 1) and the hyperparathyroidism-jaw tumour syndrome (HPT-JT). OBJECTIVE: To investigate seven families diagnosed with FIHP, each with two to eight affected family members, to clarify the underlying genetic mechanism. METHODS: The entire MEN1 gene was sequenced for germline mutations and, in addition, tumour specimens were analysed in comparative genomic hybridisation and loss of heterozygosity studies. RESULTS: Two families exhibited MEN1 mutations, L112V and 1658delG, which were associated with loss of the wild-type 11q13 alleles in all tumours analysed. In the remaining five families, no MEN1 mutation was identified. CONCLUSION: These results support the involvement of the MEN1 tumour suppressor gene in the pathogenesis of some of the FIHP kindreds. However, loss on chromosome 11 was seen in all tumours exhibiting somatic deletions, although in two families the tumour deletions involved 11q distal to MEN1. We conclude that the altered MEN1 gene function is of importance in the development of FIHP.

scholarly journals Frequent Occurrence of an Intron 4 Mutation in Multiple Endocrine Neoplasia Type 1

2002 ◽  
Vol 87 (6) ◽  
pp. 2688-2693 ◽  
Author(s):  
Jeremy J. O. Turner ◽  
Poloko D. Leotlela ◽  
Anna A. J. Pannett ◽  
Simon A. Forbes ◽  
J. H. Duncan Bassett ◽  
...  
Keyword(s):  
Splice Site ◽  
Splice Site Mutation ◽  
Pancreatic Tumors ◽  
Coding Region ◽  
Site Mutation ◽  
Autosomal Dominant Disorder ◽  
Acid Protein ◽  
Intron 4 ◽  
Amino Acid Protein

MEN1 is an autosomal dominant disorder characterized by parathyroid, pituitary, and pancreatic tumors. The MEN1 gene is located on chromosome 11q13 and encodes a 610-amino acid protein. MEN1 mutations are of diverse types and are scattered throughout the coding region, such that almost every MEN1 family will have its individual mutation. To further characterize such mutations we ascertained 34 unrelated MEN1 probands and undertook DNA sequence analysis. This identified 17 different mutations in 24 probands (2 nonsense, 2 missense, 2 in-frame deletions, 5 frameshift deletions, 1 frameshift deletional-insertion, 3 frameshift insertions, 1 donor splice site mutation, and a g→a transition that resulted in a novel acceptor splice site in intron 4). The intron 4 mutation was found in 7 unrelated families, and the tumors in these families varied considerably, indicating a lack of genotype-phenotype correlation. However, this intron 4 mutation is the most frequently occurring germline MEN1 mutation (∼10% of all mutations), and together with 5 others at codons 83–84, 118–119, 209–211, 418, and 516, accounts for 36.6% of all mutations, a finding that indicates an approach for identifying the widely diverse MEN1 mutations.

scholarly journals Germline and somatic mosaicism in a family with multiple endocrine neoplasia type 1 (MEN1) syndrome

2019 ◽  
Vol 180 (2) ◽  
pp. K15-K19 ◽  
Author(s):  
Hanneke J B H Beijers ◽  
Nike M L Stikkelbroeck ◽  
Arjen R Mensenkamp ◽  
Rolph Pfundt ◽  
Rob B van der Luijt ◽  
...  
Keyword(s):  
Multiple Endocrine Neoplasia ◽  
De Novo ◽  
Multiple Endocrine Neoplasia Type ◽  
Somatic Mosaicism ◽  
Suppressor Gene ◽  
Germline Mosaicism ◽  
Endocrine Neoplasia ◽  
Endocrine Neoplasia Type ◽  
Dominant Disease

Context Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease caused by mutations in the tumor suppressor gene MEN1 and can be diagnosed based on clinical, familial and/or genetic criteria. We present a family in which we found both germline and somatic mosaicism for MEN1. Family description In our proband, we diagnosed MEN1. The mutation was not detected in her parents (DNA extracted from leucocytes). When her brother was found to harbor the same MEN1 mutation as our proband and, around the same time, their father was diagnosed with a neuroendocrine carcinoma, this tumor was investigated for the MEN1 mutation as well. In the histologic biopsy of this tumor, the same MEN1 mutation was detected as previously found in his children. Re-analysis of his blood using multiplex ligation-dependent probe amplification (MLPA) showed a minimal, but consistently decreased signal for the MEN1-specific MLPA probes. The deletion was confirmed in his son by high-resolution array analysis. Based on the array data, we concluded that the deletion was limited to the MEN1 gene and that the father had both germline and somatic mosaicism for MEN1. Conclusions To our knowledge, this is the first reported family with combined germline and somatic mosaicism for MEN1. This study illustrates that germline mosaicism is important to consider in apparently sporadic de novo MEN1 mutations, because of its particular importance for genetic counseling, specifically when evaluating the risk for family members and when considering the possibility of somatic mosaicism in the parent with germline mosaicism.

scholarly journals Menin Missense Mutants Associated with Multiple Endocrine Neoplasia Type 1 Are Rapidly Degraded via the Ubiquitin-Proteasome Pathway

2004 ◽  
Vol 24 (15) ◽  
pp. 6569-6580 ◽  
Author(s):  
Hiroko Yaguchi ◽  
Naganari Ohkura ◽  
Maho Takahashi ◽  
Yuko Nagamura ◽  
Issay Kitabayashi ◽  
...  
Keyword(s):  
Multiple Endocrine Neoplasia ◽  
Multiple Endocrine Neoplasia Type ◽  
Suppressor Gene ◽  
Missense Mutations ◽  
Wild Type ◽  
Ubiquitin Proteasome Pathway ◽  
Endocrine Neoplasia ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

ABSTRACT MEN1 is a tumor suppressor gene that is responsible for multiple endocrine neoplasia type 1 (MEN1) and that encodes a 610-amino-acid protein, called menin. While the majority of germ line mutations identified in MEN1 patients are frameshift and nonsense mutations resulting in truncation of the menin protein, various missense mutations have been identified whose effects on menin activity are unclear. For this study, we analyzed a series of menin proteins with single amino acid alterations and found that all of the MEN1-causing missense mutations tested led to greatly diminished levels of the affected proteins in comparison with wild-type and benign polymorphic menin protein levels. We demonstrate here that the reduced levels of the mutant proteins are due to rapid degradation via the ubiquitin-proteasome pathway. Furthermore, the mutants, but not wild-type menin, interact both with the molecular chaperone Hsp70 and with the Hsp70-associated ubiquitin ligase CHIP, and the overexpression of CHIP promotes the ubiquitination of the menin mutants in vivo. These findings reveal that MEN1-causing missense mutations lead to a loss of function of menin due to enhanced proteolytic degradation, which may be a common mechanism for inactivating tumor suppressor gene products in familial cancer.

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