Heterogeneity at the 5′-End of MEN1 Transcripts

Khodaei-O'Brien, Shideh; Zablewska, Barbara; Fromaget, Maud; Bylund, Lovisa; Weber, Günther; Gaudray, Patrick

doi:10.1006/bbrc.2000.3471

Cited by 26 publications

(14 citation statements)

References 18 publications

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“…Recent studies have shown that menin interacts with a number of proteins that are involved in transcriptional regulation, genome stability, cell division and proliferation [18]. The MEN1 locus is subject to complex transcriptional regulation resulting in a ubiquitously expressed 2.9-kb transcript with several alternatively spliced isoforms, and an additional 4.2-kb transcript present in pancreas and thymus [19].…”

Section: Pituitary Tumors Associated With Men1mentioning

confidence: 99%

Clinical and molecular genetics of acromegaly: MEN1, Carney complex, McCune–Albright syndrome, familial acromegaly and genetic defects in sporadic tumors

Horvath

Stratakis

2008

Rev Endocr Metab Disord

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Pituitary tumors are among the most common neoplasms in man; they account for approximately 15% of all primary intracranial lesions (Jagannathan et al., Neurosurg Focus, 19:E4, 2005). Although almost never malignant and rarely clinically expressed, pituitary tumors may cause significant morbidity in affected patients. First, given the critical location of the gland, large tumors may lead to mass effects, and, second, proliferation of hormone-secreting pituitary cells leads to endocrine syndromes. Acromegaly results from oversecretion of growth hormone (GH) by the proliferating somatotrophs. Despite the significant efforts made over the last decade, still little is known about the genetic causes of common pituitary tumors and even less is applied from this knowledge therapeutically. In this review, we present an update on the genetic syndromes associated with pituitary adenomas and discuss the related genetic defects. We next review findings on sporadic, non-genetic, pituitary tumors with an emphasis on pathways and animal models of pituitary disease. In conclusion, we attempt to present an overall, integrative approach to the human molecular genetics of both familiar and sporadic pituitary tumors.

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Section: Pituitary Tumors Associated With Men1mentioning

confidence: 99%

Clinical and molecular genetics of acromegaly: MEN1, Carney complex, McCune–Albright syndrome, familial acromegaly and genetic defects in sporadic tumors

Horvath

Stratakis

2008

Rev Endocr Metab Disord

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“…In such cases, a search of deletions, either at larger scale or intragenic by quantitative PCR, Southern-Blot, or fluorescence in situ hybridization (FISH) will assess the syndromic diagnosis of MEN1. Secondly, 5 0 regulatory and promoter(s) regions remain unknown, despite extensive studies and evidence of complex 5 0 alternative splicing [Khodaei-O'Brien et al, 2000]. Promoter(s) mutations or methylation may represent alternative pathways of MEN1 gene inactivation.…”

Section: ]mentioning

confidence: 99%

Germline mutation profile ofMEN1in multiple endocrine neoplasia type 1: search for correlation between phenotype and the functional domains of the MEN1 protein

et al. 2002

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Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant disease characterized by endocrine tumors of the parathyroids, the pancreatic islets, and the anterior pituitary. The MEN1 gene encodes menin, a nuclear protein interacting with JunD/AP1, Smad3, NFkappaB, and other proteins involved in transcription and cell growth regulation. Here, by exhaustive sequence analysis of 170 probands/families collected through a French clinical network, we identified 165 mutations located in coding parts of the MEN1 gene, which represent 114 distinct MEN1 germline alterations. These mutations have been included in a MEN1-locus specific database available on the world wide web together with approximately 240 germline and somatic MEN1 mutations listed from international published data. Our mutation series included 56 frameshifts, 23 nonsense, 27 missense, and eight deletion or insertion in-frame mutations. Mutations were spread over the entire coding sequence. Taken together, most missense and in-frame MEN1 genomic alterations affect one or all domains of menin interacting with JunD [codons 1-40; 139-242; 323-428], Smad3 [distal to codon 478], and NFkappaB [codons 276-479], three major effectors in transcription and cell growth regulation. No correlation has been observed between genotype and MEN1 phenotype. We suggest that the knowledge of structure and location of a specific mutation has not been useful in clinical practice for the follow-up of affected patients and asymptomatic gene carriers. Our results provide the largest series of MEN1 mutations published to date. They will be a useful tool for further studies focusing on the functional effects of missense mutations and understanding which mechanisms or pathways related to multiple menin interactions might be involved in tumorigenesis of endocrine cells.

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“…The main transcript of the MEN1 gene is a 2.8-kb mRNA. However, at least six alternative transcripts have been reported with variations in their content of the 5 0 -untranslated region; none of these affect the coding region [Khodaei-O'Brien et al, 2000]. One additional very rare variant that would result in an elongation of the reading frame by 15 bases at the exon 2-intron 2 junction has also been reported [Chandrasekharappa and Teh, 2003].…”

Section: Introductionmentioning

confidence: 99%

Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene

2008

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Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the occurrence of tumors of the parathyroids, pancreas, and anterior pituitary. The MEN1 gene, which was identified in 1997, consists of 10 exons that encode a 610-amino acid protein referred to as menin. Menin is predominantly a nuclear protein that has roles in transcriptional regulation, genome stability, cell division, and proliferation. Germline mutations usually result in MEN1 or occasionally in an allelic variant referred to as familial isolated hyperparathyroidism (FIHP). MEN1 tumors frequently have loss of heterozygosity (LOH) of the MEN1 locus, which is consistent with a tumor suppressor role of MEN1. Furthermore, somatic abnormalities of MEN1 have been reported in MEN1 and non-MEN1 endocrine tumors. The clinical aspects and molecular genetics of MEN1 are reviewed together with the reported 1,336 mutations. The majority (>70%) of these mutations are predicted to lead to truncated forms of menin. The mutations are scattered throughout the>9-kb genomic sequence of the MEN1 gene. Four, which consist of c.249_252delGTCT (deletion at codons 83-84), c.1546_1547insC (insertion at codon 516), c.1378C>T (Arg460Ter), and c.628_631delACAG (deletion at codons 210-211) have been reported to occur frequently in 4.5%, 2.7%, 2.6%, and 2.5% of families, respectively. However, a comparison of the clinical features in patients and their families with the same mutations reveals an absence of phenotype-genotype correlations. The majority of MEN1 mutations are likely to disrupt the interactions of menin with other proteins and thereby alter critical events in cell cycle regulation and proliferation.

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Heterogeneity at the 5′-End of MEN1 Transcripts

Cited by 26 publications

References 18 publications

Clinical and molecular genetics of acromegaly: MEN1, Carney complex, McCune–Albright syndrome, familial acromegaly and genetic defects in sporadic tumors

Clinical and molecular genetics of acromegaly: MEN1, Carney complex, McCune–Albright syndrome, familial acromegaly and genetic defects in sporadic tumors

Germline mutation profile ofMEN1in multiple endocrine neoplasia type 1: search for correlation between phenotype and the functional domains of the MEN1 protein

Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene

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