Application of an intracellular stability test of a novel missense menin mutant to the diagnosis of multiple endocrine neoplasia type 1

Nagamura, Yuko; Yamazaki, Masanori; Shimazu, Satoko; Tsukada, Toshihiko; Sakurai, Akihiro

doi:10.1507/endocrj.ej12-0145

Cited by 4 publications

(4 citation statements)

References 19 publications

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“…Generally, when a missense mutation is identified in an affected subject, it is necessary to evaluate its pathogenicity (7). The confirmation of the pathogenicity of these mutations remains very challenging in the clinical setting, although various methods to analyze their pathogenicity have been reported (7). LOH in the pancreatic neuroendocrine tumor provided strong evidence that the mutation was responsible for tumorigenesis in the present case (11).…”

Section: Discussionmentioning

confidence: 71%

“…To the best of our knowledge, this mutation has not been previously reported (10) or registered in The Human Gene Mutation Database (HGMD ). Generally, when a missense mutation is identified in an affected subject, it is necessary to evaluate its pathogenicity (7). The confirmation of the pathogenicity of these mutations remains very challenging in the clinical setting, although various methods to analyze their pathogenicity have been reported (7).…”

Section: Discussionmentioning

confidence: 99%

“…As previously reported, 20-30% of the germline MEN1 mutations are missense mutations (2,5). However, the confirmation of the pathogenicity of these mutations remains very challenging in clinical settings (7). Therefore, the accumulation of pathogenic missense MEN1 gene mutations should prove valuable for clinicians.…”

Section: Introductionmentioning

confidence: 95%

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A Novel Missense Mutation of the <i>MEN1</i> Gene in a Patient with Multiple Endocrine Neoplasia Type 1 with Glucagonoma and Obesity

et al. 2015

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A 35-year-old obese diabetic man presented with recurrent primary hyperparathyroidism during a threeyear outpatient follow-up. He was clinically diagnosed with multiple endocrine neoplasia type 1 (MEN1) due to the presence of a pituitary adenoma and multiple glucagonomas. The glucagonomas may have affected his glycemic control. However, he did not demonstrate weight loss, suggesting that the patient's obesity could have obscured the early diagnosis of a glucagonoma. Genetic testing revealed a novel missense mutation at codon 561 in exon 10, resulting in an amino acid substitution from methionine to arginine (M561R) in the MEN1 gene. This mutation appeared to be responsible for the MEN1 pathogenicity.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

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A Novel Missense Mutation of the <i>MEN1</i> Gene in a Patient with Multiple Endocrine Neoplasia Type 1 with Glucagonoma and Obesity

et al. 2015

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“…In addition, it suggests that the age at disease onset in the setting of AIP muts can be determined by the amount of functional protein available. The application of a protein stability assay as a means to evaluate the pathogenic effect of missense variants has also been proposed for MEN1 ( 32 , 33 ), and for PRKAR1A ( 34 ), two genes implicated in endocrine tumor-predisposing syndromes. Nevertheless, protein stability is a parameter that cannot be evaluated with routine diagnostic histopathological procedures.…”

Section: Discussionmentioning

confidence: 99%

Rapid Proteasomal Degradation of Mutant Proteins Is the Primary Mechanism Leading to Tumorigenesis in Patients With MissenseAIPMutations

Hernández-Ramírez¹,

Martucci²,

Morgan

et al. 2016

The Journal of Clinical Endocrinology & Metabolism

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Context:The pathogenic effect of mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene (AIPmuts) in pituitary adenomas is incompletely understood. We have identified the primary mechanism of loss of function for missense AIPmuts.Objective:This study sought to analyze the mechanism/speed of protein turnover of wild-type and missense AIP variants, correlating protein half-life with clinical parameters.Design and Setting:Half-life and protein–protein interaction experiments and cross-sectional analysis of AIPmut positive patients' data were performed in a clinical academic research institution.Patients:Data were obtained from our cohort of pituitary adenoma patients and literature-reported cases.Interventions:Protein turnover of endogenous AIP in two cell lines and fifteen AIP variants overexpressed in HEK293 cells was analyzed via cycloheximide chase and proteasome inhibition. Glutathione-S-transferase pull-down and quantitative mass spectrometry identified proteins involved in AIP degradation; results were confirmed by coimmunoprecipitation and gene knockdown. Relevant clinical data was collected.Main Outcome Measures:Half-life of wild-type and mutant AIP proteins and its correlation with clinical parameters.Results:Endogenous AIP half-life was similar in HEK293 and lymphoblastoid cells (43.5 and 32.7 h). AIP variants were divided into stable proteins (median, 77.7 h; interquartile range [IQR], 60.7–92.9 h), and those with short (median, 27 h; IQR, 21.6–28.7 h) or very short (median, 7.7 h; IQR, 5.6–10.5 h) half-life; proteasomal inhibition rescued the rapid degradation of mutant proteins. The experimental half-life significantly correlated with age at diagnosis of acromegaly/gigantism (r = 0.411; P = .002). The FBXO3-containing SKP1–CUL1–F-box protein complex was identified as the E3 ubiquitin-ligase recognizing AIP.Conclusions:AIP is a stable protein, driven to ubiquitination by the SKP1–CUL1–F-box protein complex. Enhanced proteasomal degradation is a novel pathogenic mechanism for AIPmuts, with direct implications for the phenotype.

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Pathophysiology of Gastric NETs: Role of Gastrin and Menin

Sundaresan

Kang

Merchant

2017

Curr Gastroenterol Rep

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Neuroendocrine tumors (NETs) were initially identified as a separate entity in the early 1900s as a unique malignancy that secretes bioactive amines. GI-NETs are the most frequent type, and represent a unique subset of NETs because at least 75% of these tumors represent gastrin stimulation of the enterochromaffin-like cell located in the body of the stomach. Purpose of Review To understand the specific role of gastrin in the generation of Gastric NETs (G-NETs). Recent Findings We review here the origin of enterochromaffin cells gut and the role of hypergastrinemia in gastric enteroendocrine tumorigenesis. We describe generation of the first genetically engineered mouse model of gastrin-driven G-NETs that mimics the human phenotype. The common mechanism observed in both the hypergastrinemic mouse model and human carcinoids is translocation of the cyclin-dependent inhibitor p27kip to the cytoplasm and its subsequent degradation by the proteasome. Summary Therapies that block degradation of p27kip, the CCKBR2 gastrin receptor or gastrin peptide are likely to facilitate treatment.

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Application of an intracellular stability test of a novel missense menin mutant to the diagnosis of multiple endocrine neoplasia type 1

Cited by 4 publications

References 19 publications

A Novel Missense Mutation of the <i>MEN1</i> Gene in a Patient with Multiple Endocrine Neoplasia Type 1 with Glucagonoma and Obesity

A Novel Missense Mutation of the <i>MEN1</i> Gene in a Patient with Multiple Endocrine Neoplasia Type 1 with Glucagonoma and Obesity

Rapid Proteasomal Degradation of Mutant Proteins Is the Primary Mechanism Leading to Tumorigenesis in Patients With MissenseAIPMutations

Pathophysiology of Gastric NETs: Role of Gastrin and Menin

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