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 Homozygous inactivation of the MEN1 gene as a specific somatic event in a case of secondary hyperparathyroidism

2001 ◽  
pp. 415-420 ◽  
Author(s):  
L Forsberg ◽  
A Villablanca ◽  
S Valimaki ◽  
F Farnebo ◽  
LO Farnebo ◽  
...  
Keyword(s):  
Secondary Hyperparathyroidism ◽  
Suppressor Gene ◽  
Genetic Alterations ◽  
Comparative Genomic ◽  
Coding Region ◽  
Chromosome 11 ◽  
Chromosomal Alterations ◽  
Men1 Gene ◽  
Genetic Mechanisms

BACKGROUND: Most patients who have been surgically treated for secondary hyperparathyroidism (HPT) harbor at least one pathological parathyroid gland with a tumor of monoclonal origin. OBJECTIVE: To elucidate the underlying genetic mechanisms behind secondary HPT, by studying a panel of such tumors for numerical alterations. METHODS: Sixteen parathyroid glands from eight patients (median age 58 years, range 31-74 years), were screened for numerical chromosomal imbalances, using comparative genomic hybridization (CGH). Mutation analysis of the multiple endocrine neoplasia type 1 gene (MEN1) was also performed by sequencing of the coding region. RESULTS: The results show that gross chromosomal alterations occur rarely in secondary HPT. In one of the three glands analyzed from one patient, a complete loss of chromosome 11 was detected. This gland also had an inactivating nonsense mutation, E469X, of the MEN1 gene. The mutation was present neither in the other two glands, nor in the constitutional tissue of the same patient, thus confirming its somatic origin. CONCLUSIONS: The relative lack of numerical chromosomal alterations would suggest that more discrete genetic alterations are responsible for the monoclonal growth in the majority of cases of secondary HPT. Furthermore, somatic inactivation of the MEN1 tumor suppressor gene contributes to the tumorigenesis in a small proportion of the cases.

Constitutional de novo deletion CNV encompassing REST predisposes to diffuse hyperplastic perilobar nephroblastomatosis (HPLN)

2020 ◽  
pp. jmedgenet-2020-107087
Author(s):  
Zerin Hyder ◽  
Adele Fairclough ◽  
Mike Groom ◽  
Joan Getty ◽  
Elizabeth Alexander ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
De Novo ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Cancer Predisposition ◽  
Tumour Suppressor ◽  
Comparative Genomic Hybridisation ◽  
Comparative Genomic ◽  
Predisposition Genes ◽  
Work Up

BackgroundNephroblastomatosis is a recognised precursor for the development of Wilms tumour (WT), the most common childhood renal tumour. While the majority of WT is sporadic in origin, germline intragenic mutations of predisposition genes such as WT1, REST and TRIM28 have been described in apparently isolated (non-familial) WT.Despite constitutional CNVs being a well-studied cause of developmental disorders, their role in cancer predisposition is less well defined, so that the interpretation of cancer risks associated with specific CNVs can be complex.ObjectiveTo highlight the role of a constitutional deletion CNV (delCNV) encompassing the REST tumour suppressor gene in diffuse hyperplastic perilobar nephroblastomatosis (HPLN).Methods/resultsArray comparative genomic hybridisation in an infant presenting with apparently sporadic diffuse HPLN revealed a de novo germline CNV, arr[GRCh37] 4q12(57,385,330–57,947,405)x1. The REST tumour suppressor gene is located at GRCh37 chr4:57,774,042–57,802,010.ConclusionThis delCNV encompassing REST is associated with nephroblastomatosis. Deletion studies should be included in the molecular work-up of inherited predisposition to WT/nephroblastomatosis. Detection of delCNVs involving known cancer predisposition genes can yield insights into the relationship between underlying genomic architecture and associated tumour risk.

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.

scholarly journals Loss of Wild-Type MEN1 Gene Expression in Multiple Endocrine Neoplasia Type 1-Associated Parathyroid Adenoma.

1999 ◽  
Vol 46 (4) ◽  
pp. 539-544 ◽  
Author(s):  
LEOPOLD LUDWIG ◽  
LOTHAR SCHLEITHOFF ◽  
HEIDI KESSLER ◽  
PETER K. WAGNER ◽  
BERNHARD O. BOEHM ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parathyroid Adenoma ◽  
Multiple Endocrine Neoplasia ◽  
Multiple Endocrine Neoplasia Type ◽  
Wild Type ◽  
Men1 Gene ◽  
Endocrine Neoplasia ◽  
Endocrine Neoplasia Type

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 Role of miR-24 in Multiple Endocrine Neoplasia Type 1: A Potential Target for Molecular Therapy

2021 ◽  
Vol 22 (14) ◽  
pp. 7352
Author(s):  
Francesca Marini ◽  
Maria Luisa Brandi
Keyword(s):  
Multiple Endocrine Neoplasia ◽  
Multiple Endocrine Neoplasia Type ◽  
Current Knowledge ◽  
Neuroendocrine Cells ◽  
Molecular Therapy ◽  
Multiple Cancer ◽  
Men1 Gene ◽  
Endocrine Neoplasia ◽  
Endocrine Neoplasia Type

Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant inherited multiple cancer syndrome of neuroendocrine tissues. Tumors are caused by an inherited germinal heterozygote inactivating mutation of the MEN1 tumor suppressor gene, followed by a somatic loss of heterozygosity (LOH) of the MEN1 gene in target neuroendocrine cells, mainly at parathyroids, pancreas islets, and anterior pituitary. Over 1,500 different germline and somatic mutations of the MEN1 gene have been identified, but the syndrome is completely missing a direct genotype-phenotype correlation, thus supporting the hypothesis that exogenous and endogenous factors, other than MEN1 specific mutation, are involved in MEN1 tumorigenesis and definition of individual clinical phenotype. Epigenetic factors, such as microRNAs (miRNAs), are strongly suspected to have a role in MEN1 tumor initiation and development. Recently, a direct autoregulatory network between miR-24, MEN1 mRNA, and menin was demonstrated in parathyroids and endocrine pancreas, showing a miR-24-induced silencing of menin expression that could have a key role in initiation of tumors in MEN1-target neuroendocrine cells. Here, we review the current knowledge on the post-transcriptional regulation of MEN1 and menin expression by miR-24, and its possible direct role in MEN1 syndrome, describing the possibility and the potential approaches to target and silence this miRNA, to permit the correct expression of the wild type menin, and thereby prevent the development of cancers in the target tissues.

scholarly journals Germline MEN1 mutations in sixteen Japanese families with multiple endocrine neoplasia type 1 (MEN1)

1999 ◽  
pp. 475-480 ◽  
Author(s):  
N Hai ◽  
N Aoki ◽  
A Matsuda ◽  
T Mori ◽  
S Kosugi
Keyword(s):  
Multiple Endocrine Neoplasia ◽  
Multiple Endocrine Neoplasia Type ◽  
Family Members ◽  
Premature Stop Codon ◽  
Germline Mutations ◽  
Endocrine Tumors ◽  
Men1 Gene ◽  
Endocrine Neoplasia ◽  
Endocrine Neoplasia Type

OBJECTIVE: Multiple endocrine neoplasia type 1 (MEN1) is a syndrome of endocrine tumors involving the parathyroids, anterior pituitary and enteropancreatic neuroendocrine tissues, and is inherited in an autosomal dominant manner. Recently, the gene responsible for this syndrome, MEN1, was positionally cloned in 11q13. We aimed to assess the significance of MEN1 gene diagnostics in families with MEN1. DESIGN: Sixteen probands of familial MEN1 and their 40 family members were subjected to the study. METHODS: Full-length sequencing of the open reading frame and exon-intron boundaries in the MEN1 gene was performed with probands of familial MEN1. Family members were examined for the identified mutation in the proband. RESULTS: We identified heterozygous germline mutations of the MEN1 gene in all of 16 Japanese MEN1 families examined, achieving the highest detectability of MEN1 mutations in familial MEN1 among studies that examined more than 10 families. Eleven kinds of the identified MEN1 germline mutations were novel. More than half were nonsense or frameshift mutations resulting in a premature stop codon (9/15; 60%), and no mutation hot spots or no apparent genotype-phenotype relationships were observed, in support of the results of other studies. We identified 40 mutant MEN1 gene carriers and 16 non-carriers in the course of the present study in those families. CONCLUSIONS: Analysis of the germline mutations in the MEN1 gene, providing significantly useful clinical information to probands and family members of MEN1, should be considered as a standard procedure and categorized as belonging to Group 1 cancer predisposition testing by the American Society of Clinical Oncology.

scholarly journals Multiple endocrine neoplasia type 1 (MEN1) gene mutations in a subset of patients with sporadic and familial primary hyperparathyroidism target the coding sequence but spare the promoter region

2000 ◽  
Vol 166 (1) ◽  
pp. 1-9 ◽  
Author(s):  
W Karges ◽  
K Jostarndt ◽  
S Maier ◽  
A Flemming ◽  
M Weitz ◽  
...  
Keyword(s):  
Multiple Endocrine Neoplasia ◽  
Multiple Endocrine Neoplasia Type ◽  
Germ Line ◽  
Single Strand Conformational Polymorphism ◽  
Coding Sequence ◽  
Men1 Gene ◽  
Endocrine Neoplasia ◽  
Endocrine Neoplasia Type ◽  
Germ Line Mutations

Germ line mutations of the multiple endocrine neoplasia type 1 (MEN1) tumour suppressor gene cause MEN1, a rare familial tumour syndrome associated with parathyroid hyperplasia, adenoma and hyperparathyroidism (HP). Here we investigated the role of the MEN1 gene in isolated sporadic and familial HP. Using RT-PCR single-strand conformational polymorphism screening, somatic (but not germ line) mutations of the MEN1 coding sequence were identified in 6 of 31 (19.3%) adenomas from patients with sporadic primary HP, but none in patients (n=16) with secondary HP due to chronic renal failure. MEN1 mutations were accompanied by a loss of heterozygosity (LOH) for the MEN1 locus on chromosome 11q13 in the adenomas as detected by microsatellite analysis. No DNA sequence divergence within the 5' region of the MEN1 gene, containing the putative MEN1 promoter, was detectable in HP adenomas. Clinical characteristics were not different in HP patients with or without MEN1 mutation. Heterozygous MEN1 gene polymorphisms were identified in 9.6% and 25% of patients with primary and secondary HP respectively. In a large kindred with familial isolated familial HP, MEN1 germ line mutation 249 del4 and LOH was associated with the HP phenotype and a predisposition to non-endocrine malignancies. We suggest that the bi-allelic somatic loss of MEN1 wild-type gene expression is involved in the pathogenesis of a clinically yet undefined subset of sporadic primary HP adenomas. MEN1 genotyping may further help define the familial hyperparathyroidism-MEN1 disease complex, but it seems dispensable in sporadic primary HP.

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