Investigating the Effects of Amino Acid Variations in Human Menin

Biancaniello, Carmen; D’Argenio, Antonia; Giordano, Deborah; Dotolo, Serena; Scafuri, Bernardina; d’Acierno, Antonio; Tagliaferri, Roberto; Facchiano, Angelo

doi:10.3390/molecules27051747

Cited by 10 publications

(8 citation statements)

References 57 publications

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“…To date, many studies regarding pathogenic variants in the MEN1 gene have been published [ 4 , 5 ]. According to several protein–protein interaction studies, pathogenic variants in the MEN1 gene may affect the interaction between menin and related proteins [ 6 ]. Approximately 25% of pathogenic variants in the MEN1 gene are missense variants whose effects on the protein's structure and function have not yet been determined [ 8 ].…”

Section: Discussionmentioning

confidence: 99%

“…The MEN1 gene was identified in 1997, and since then, more than 770 different germline and somatic pathogenic variants have been identified [ 4 , 5 ]. Menin is involved in various biological processes, including transcriptional regulation; DNA damage repair; and cell signaling, division, proliferation, and migration [ 6 ]. The MEN1 gene functions as a tumor suppressor, and loss-of-function variants lead to the development of MEN1.…”

Section: Introductionmentioning

confidence: 99%

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A Novel Pathogenic MEN1 Gene Variant Identified in a Family With Multiple Pancreatic Neuroendocrine Tumors

et al. 2023

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Multiple endocrine neoplasia type 1 (MEN1) is a hereditary endocrine tumor syndrome caused by pathogenic variants in the MEN1 gene, and most patients with this syndrome initially develop primary hyperparathyroidism (PHPT). Here, we report the case of a family wherein a germline MEN1 variant was detected and multiple pancreatic neuroendocrine tumors (PanNETs) were observed at the initial evaluation. A 40-year-old woman presented with a complaint of abdominal discomfort, and a close examination revealed multiple pancreatic tumors. Distal pancreatectomy with splenectomy was performed, and the diagnosis was nonfunctional PanNETs. Five years later, her 76-year-old mother was referred to the hospital with multiple pancreatic tumors. A genetic test revealed that both patients harbored a previously unreported germline variant in the MEN1 gene. Although it was classified as a variant of uncertain significance, we suspect that it may be associated with the pathogenesis of these lesions. This case report presents a new disease concept—familial isolated pancreatic neuroendocrine tumors, or FIPNETs—in patients harboring a pathogenic variant in the MEN1 gene who experience only pancreatic lesions. We suggest that clinicians consider genetic testing for the MEN1 gene in patients with multiple pancreatic lesions who show no signs of PHPT.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Novel Pathogenic MEN1 Gene Variant Identified in a Family With Multiple Pancreatic Neuroendocrine Tumors

et al. 2023

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“…Taken together, the nuclear interactome data of our MEN1 mutant set indicate a pathological role for six out of nine menin mutations tested. In two recent studies, MEN1 gene missense mutations were analyzed in different in silico approach to predict unstable menin mutants [ 37 , 38 ]. In contrast, we combined in silico predictions for stable menin mutants with transient and stable expression in HeLa cell and quantitative mass spectrometry to identify deficient functions of these mutants.…”

Section: Discussionmentioning

confidence: 99%

Multi-omics analyses of MEN1 missense mutations identify disruption of menin–MLL and menin–JunD interactions as critical requirements for molecular pathogenicity

Dreijerink

Ozyerli-Goknar

Koidl

et al. 2022

Epigenetics & Chromatin

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Background Loss-of-function mutations of the multiple endocrine neoplasia type 1 (MEN1) gene are causal to the MEN1 tumor syndrome, but they are also commonly found in sporadic pancreatic neuroendocrine tumors and other types of cancers. The MEN1 gene product, menin, is involved in transcriptional and chromatin regulation, most prominently as an integral component of KMT2A/MLL1 and KMT2B/MLL2 containing COMPASS-like histone H3K4 methyltransferase complexes. In a mutually exclusive fashion, menin also interacts with the JunD subunit of the AP-1 and ATF/CREB transcription factors. Results Here, we applied and in silico screening approach for 253 disease-related MEN1 missense mutations in order to select a set of nine menin mutations in surface-exposed residues. The protein interactomes of these mutants were assessed by quantitative mass spectrometry, which indicated that seven of the nine mutants disrupt interactions with both MLL1/MLL2 and JunD complexes. Interestingly, we identified three missense mutations, R52G, E255K and E359K, which predominantly reduce the MLL1 and MLL2 interactions when compared with JunD. This observation was supported by a pronounced loss of binding of the R52G, E255K and E359K mutant proteins at unique MLL1 genomic binding sites with less effect on unique JunD sites. Conclusions Our results underline the effects of MEN1 gene mutations in both familial and sporadic tumors of endocrine origin on the interactions of menin with the MLL1 and MLL2 histone H3K4 methyltransferase complexes and with JunD-containing transcription factors. Menin binding pocket mutants R52G, E255K and E359K have differential effects on MLL1/MLL2 and JunD interactions, which translate into differential genomic binding patterns. Our findings encourage future studies addressing the pathophysiological relevance of the separate MLL1/MLL2- and JunD-dependent functions of menin mutants in MEN1 disease model systems.

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“…Taken together, the nuclear interactome data of our MEN1 mutant set indicates a pathological role for six out of nine menin mutations tested. In two recent studies MEN1 gene missense mutations were analyzed in different in silico approach to predict unstable menin mutants (Biancaniello et al , 2022; Caswell et al , 2019). In contrast, we combined in silico predictions for stable menin mutants with transient and stable expression in HeLa cell and quantitative mass spectrometry to identify deficient functions of these mutants.…”

Section: Discussionmentioning

confidence: 99%

Multi-omics analyses of MEN1 missense mutations identify disruption of menin-MLL and menin-JunD interactions as critical requirements for molecular pathogenicity

Dreijerink

Ozyerli-Goknar

Koidl

et al. 2022

Preprint

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Loss-of-function mutations of the multiple endocrine neoplasia type 1 (MEN1) gene are causal to the MEN1 tumor syndrome, but they are also commonly found in sporadic pancreatic neuroendocrine tumors and other types of cancers. The MEN1 gene product, menin, is involved in transcriptional and chromatin regulation, most prominently as an integral component of KMT2A/MLL1 and KMT2B/MLL2 containing COMPASS-like histone H3K4 methyltransferase complexes. In a mutually exclusive fashion, menin also interacts with the JunD subunit of the AP-1 and ATF/CREB transcription factors. After in silico screening of 253 disease-related MEN1 missense mutations, we selected a set of nine menin mutations in surface-exposed residues. The protein interactomes of these mutants were assessed by quantitative mass spectrometry, which indicated that seven of the nine mutants disrupt interactions with both MLL1/2 and JunD complexes. Interestingly, we identified three missense mutations, R52G, E255K and E359K, which predominantly reduce the interaction with MLL1 compared to JunD. This observation was supported by a pronounced loss of binding of the R52G, E255K and E359K mutant proteins at unique MLL1 genomic binding sites with less effect on unique JunD sites. These findings support the general importance of the menin-MLL1 and menin-JunD interactions in MEN1 gene-associated pathogenic conditions.

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Investigating the Effects of Amino Acid Variations in Human Menin

Cited by 10 publications

References 57 publications

A Novel Pathogenic MEN1 Gene Variant Identified in a Family With Multiple Pancreatic Neuroendocrine Tumors

A Novel Pathogenic MEN1 Gene Variant Identified in a Family With Multiple Pancreatic Neuroendocrine Tumors

Multi-omics analyses of MEN1 missense mutations identify disruption of menin–MLL and menin–JunD interactions as critical requirements for molecular pathogenicity

Multi-omics analyses of MEN1 missense mutations identify disruption of menin-MLL and menin-JunD interactions as critical requirements for molecular pathogenicity

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