Multiple endocrine neoplasia type 1 knockout mice develop parathyroid, pancreatic, pituitary and adrenal tumours with hypercalcaemia, hypophosphataemia and hypercorticosteronaemia

Harding, Brian; Lemos, Manuel C.; Reed, Anita; Walls, Gerard; Jeyabalan, Jeshmi; Bowl, Michael R.; Tateossian, Hilda; Sullivan, Nicky; Hough, Tertius; Fraser, William D.; Ansorge, Olaf; Cheeseman, Michael; Thakker, Rajesh V.

doi:10.1677/erc-09-0082

Cited by 88 publications

(123 citation statements)

References 36 publications

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“…However, great caution must be exercised because β-cell hyperplasia, insulinomas, and hyperinsulinemia have been detected in Men1 knockout mouse models and in MEN1 patients (5,6,8,31). This finding raises a substantial concern that permanent menin inhibition as a therapeutic approach may eventually lead to insulinomas (6,32). If the aforementioned situation is the case, targeting menin itself as a means to treat diabetes would not be viable.…”

Section: Discussionmentioning

confidence: 99%

Reversal of preexisting hyperglycemia in diabetic mice by acute deletion of the Men1 gene

Yang

Gurung

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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A hallmark of diabetes is an absolute or relative reduction in the number of functional β cells. Therapies that could increase the number of endogenous β cells under diabetic conditions would be desirable. Prevalent gene targeting mouse models for assessing β-cell proliferation and diabetes pathogenesis only address whether deletion of a gene prevents the development of diabetes. Models testing whether acute excision of a single gene can ameliorate or reverse preexisting hyperglycemia in established diabetes remain to be explored, which could directly validate the effect of gene excision on treating diabetes. Here, we report that acute and temporally controlled excision of the Men1 gene, which encodes menin, ameliorated preexisting hyperglycemia in streptozotocin-treated mice. Moreover, Men1 excision also improved the preexisting hyperglycemia and glucose intolerance in genetic db/db diabetic mice. Furthermore, acute Men1 excision reversed preexisting glucose intolerance in high-fat diet-fed mice. Men1 excision improved glucose metabolism at least partly through increasing proliferation of endogenous β cells and islet size. Acute Men1 excision up-regulated a group of proproliferative genes in pancreatic islets. Together, these findings demonstrate that established hyperglycemia can be reversed through repression of a single gene, Men1, in diabetic conditions, and suggest that menin is a vital regulator in pathogenesis of diabetes.cell proliferation | db/db | high-fat diet | type 2 diabetes

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Section: Discussionmentioning

confidence: 99%

Reversal of preexisting hyperglycemia in diabetic mice by acute deletion of the Men1 gene

Yang

Gurung

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Food and water were allowed ad libitum. Blood was collected for analysis of plasma using an Olympus AU400 analyzer, as described (50). PTH was measured using an ELISA for mouse intact PTH (Immutopics), as described (50).…”

Section: Methodsmentioning

confidence: 99%

“…Blood was collected for analysis of plasma using an Olympus AU400 analyzer, as described (50). PTH was measured using an ELISA for mouse intact PTH (Immutopics), as described (50). The trachea, thyroid, and parathyroid were block dissected and fixed overnight in 10% neutral formalin.…”

Section: Methodsmentioning

confidence: 99%

Gata3-deficient mice develop parathyroid abnormalities due to dysregulation of the parathyroid-specific transcription factor Gcm2

Grigorieva¹,

Mirczuk²,

Gaynor³

et al. 2010

J. Clin. Invest.

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116

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Heterozygous mutations of GATA3, which encodes a dual zinc-finger transcription factor, cause hypoparathyroidism with sensorineural deafness and renal dysplasia. Here, we have investigated the role of GATA3 in parathyroid function by challenging Gata3 +/-mice with a diet low in calcium and vitamin D so as to expose any defects in parathyroid function. This led to a higher mortality among Gata3 +/-mice compared with Gata3 +/+ mice. Compared with their wild-type littermates, Gata3 +/-mice had lower plasma concentrations of calcium and parathyroid hormone (PTH) and smaller parathyroid glands with a reduced Ki-67 proliferation rate. At E11.5, Gata3 +/-embryos had smaller parathyroid-thymus primordia with fewer cells expressing the parathyroid-specific gene glial cells missing 2 (Gcm2), the homolog of human GCMB. In contrast, E11.5 Gata3 -/-embryos had no Gcm2 expression and by E12.5 had gross defects in the third and fourth pharyngeal pouches, including absent parathyroid-thymus primordia. Electrophoretic mobility shift, luciferase reporter, and chromatin immunoprecipitation assays showed that GATA3 binds specifically to a functional double-GATA motif within the GCMB promoter. Thus, GATA3 is critical for the differentiation and survival of parathyroid progenitor cells and, with GCM2/B, forms part of a transcriptional cascade in parathyroid development and function.

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“…MEN1 is a tumor suppressor gene involved in cellular functions as cell cycle and proliferation (35). Knockout mice with deletion of certain exons developed adrenal tumors or hyperplasia that could be bilateral or associated with corticosterone secretion (36). Finally, PBMAH could be considered as one of the manifestations of MEN1.…”

Section: European Journal Of Endocrinologymentioning

confidence: 99%

Genetics of primary bilateral macronodular adrenal hyperplasia: a model for early diagnosis of Cushing's syndrome?

Drougat

Espiard

Bertherat

2015

European Journal of Endocrinology

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Long-term consequences of cortisol excess are frequent despite appropriate treatment after cure of Cushing's syndrome. This might be due to diagnostic delay, often difficult to reduce in rare diseases. The identification of a genetic predisposing factor might help to improve early diagnosis by familial screening. Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing's syndrome. Hypercortisolism in PBMAH is most often diagnosed between the fifth and sixth decades of life. The bilateral nature of the adrenocortical tumors and the occurrence of rare clear familial forms suggest a genetic origin. Indeed, a limited subset of PBMAH can be observed as part of multiple tumors syndromes due to alterations of the APC, Menin or Fumarate Hydratase genes. Rare variants of the phosphodiesterases PDE11A have been associated with PBMAH. The recent identification of ARMC5 germline alterations in 25-50% of PBMAH patients without obvious familial history or associated tumors opens new perspectives. ARMC5 alterations follow the model of a tumor suppressor gene: a first germline inactivating mutation of this 16p located gene is followed by a somatic secondary hit on the other allele (inactivating mutation or allelic loss). Functional studies demonstrate that ARMC5 controls apoptosis and steroid synthesis. The phenotype of index cases patients with the mutation seems more severe than the one of WT index cases. However, phenotype variability within a family is often observed. This review summarizes the genetics of PBMAH, focusing on ARMC5, which offer new perspectives for early diagnosis of Cushing's syndrome.

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Multiple endocrine neoplasia type 1 knockout mice develop parathyroid, pancreatic, pituitary and adrenal tumours with hypercalcaemia, hypophosphataemia and hypercorticosteronaemia

Cited by 88 publications

References 36 publications

Reversal of preexisting hyperglycemia in diabetic mice by acute deletion of the Men1 gene

Reversal of preexisting hyperglycemia in diabetic mice by acute deletion of the Men1 gene

Gata3-deficient mice develop parathyroid abnormalities due to dysregulation of the parathyroid-specific transcription factor Gcm2

Genetics of primary bilateral macronodular adrenal hyperplasia: a model for early diagnosis of Cushing's syndrome?

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