Characterization of Mutations in Patients with Multiple Endocrine Neoplasia Type 1

Bassett, J. H. Duncan; Forbes, S. A.; Pannett, A. A. J.; Lloyd, Sarah E.; Christie, Paul T.; Wooding, C; Harding, Brian; Besser, G. M.; Edwards, Caitlin; Monson, JP; Sampson, Julian R.; Wass, John; Wheeler, Malcolm H.; Thakker, Rajesh V.

doi:10.1086/301729

Cited by 407 publications

(382 citation statements)

References 31 publications

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“…Indeed, the penetrance of MEN1 for 20-and 25-year-old mutation carriers is estimated around 52% and 78%, respectively. 12 Genetic testing permitted to enable a strict follow-up for these two patients and to avoid periodic screening of non-carriers.…”

Section: Resultsmentioning

confidence: 99%

A MEN1 syndrome with a paraganglioma

et al. 2013

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Germline mutations of the MEN1 gene cause multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder characterized by tumors of the parathyroids, the pancreas, and the anterior pituitary. Paraganglioma (PGL) is a rare endocrine tumor, which can be sporadic or genetically determined. To date, PGL has never been reported as a feature of MEN1. We report here a patient presenting three features of MEN1 syndrome (hyperparathyroidism, pancreatic neuroendocrine tumor, and adrenocortical adenoma) associated with PGL. Genetic analysis of MEN1 gene revealed a new missense mutation in exon 5 (AGG-AAG), causing the substitution of arginine by lysine at codon 275. Screening for other genetic disorders (SDHx, TMEM127, MAX, CDKN1B) causing PGL was negative. Immunohistochemical analyses showed normal levels of succinate dehydrogenase (SDH)A and SDHB in the PGL. The proband's sister, bearing the mutation, had primary hyperparathyroidism. It was the first typical MEN1 syndrome reported with an extra-adrenal PGL.

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Section: Resultsmentioning

confidence: 99%

A MEN1 syndrome with a paraganglioma

et al. 2013

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“…The position of the epitope recognized by the antibody M1C2 is underlined. Below are indicated the position of constitutional (c) and somatic (s) missense mutations and single amino acid deletions detected in MEN 1 patients Agarwal et al, 1997;Bassett et al, 1998;Teh et al, 1998) and sporadic parathyroid Farnebo et al, 1998), pancreatic-duodenal (Toilat et al, 1997;Zhuang et al, 1997b) and pituitary tumours. For some amino acids more than one mutation was found, and the number is given in parenthesis (2 or 3) Uppercase and lowercase letters denote exonic and intronic sequences, respectively.…”

Section: Rna and Protein Expressionmentioning

confidence: 99%

Characterization of the mouse Men1 gene and its expression during development

et al. 1998

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The gene responsible for multiple endocrine neoplasia type 1 (MEN1), a heritable predisposition to endocrine tumours in man, has recently been identi®ed. Here we have characterized the murine homologue with regard to cDNA sequence, genomic structure, expression pattern and chromosomal localisation. The murine Men1 gene spans approximately 6.7 kb of genomic DNA and is comprised of 10 exons with similar genomic structure to the human locus. It was mapped to the pericentromeric region of mouse chromosome 19, which is conserved with the human 11q13 band where MEN1 is located. The predicted protein is 611 amino acids in length and overall is 97% homologous to the human orthologue. The 45 reported MEN1 mutations which alter or delete a single amino acid in human all occur at conserved residues, thereby supporting their functional signi®cance. Two transcripts of approximately 3.2 and 2.8 kb were detected in both embryonal and adult murine tissues, resulting from alternative splicing of intron 1. By RNA in situ hybridization and Northern analysis the spatiotemporal expression pattern of Men1 was determined during mouse development. Men1 gene activity was detected already at gestational day 7. At embryonic day 14 expression was generally high throughout the embryo, while at day 17 the thymus, skeletal muscle, and CNS showed the strongest signal. In selected tissues from postnatal mouse Men1 was detected in all tissues analysed and was expressed at high levels in cerebral cortex, hippocampus, testis, and thymus. In brain the menin protein was detected mainly in nerve cell nuclei, whereas in testis it appeared perinuclear in spermatogonia. These results show that Men1 expression is not con®ned to organs a ected in MEN1, suggesting that Men1 has a signi®cant function in many di erent cell types including the CNS and testis.

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“…In addition, the patient was negative for all mutations known to cause MEN1, although about 5–15% of considered MEN1 cases are genetically unverified 17, 23, 24. Furthermore, only the index patient had affection of more than one organ, and as the penetrance of MEN1 is close to 100% in patients older than 50 years, it is unlikely that the 71‐year‐old father should be unaffected 20, 25. The low CCCR is also not typical for PHPT, but can occur due to low vitamin D. According to Thakker et al, MEN1 phenocopies are seen in up to 10% of cases with the causative mutations found in other genes including CDC73 and CASR .…”

Section: Discussionmentioning

confidence: 99%