Constitutive activation of the human ACTH receptor resulting from a synergistic interaction between two naturally occurring missense mutations in the MC2R gene

Swords, Francesca; Noon, Luke A.; King, Peter; Clark, Adrian

doi:10.1016/j.mce.2003.10.052

Cited by 56 publications

(33 citation statements)

References 22 publications

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“…In McCune-Albright syndrome, or in rare cases of BMAH, activating mutations of the Gsa subunit of heterotrimeric G protein also termed gsp mutations (GNAS) occur in a mosaic pattern in the adrenal during early embryogenesis resulting in constitutive activation of the cAMP pathway (19,20,21,22). In BMAH, activating mutations in MC2R gene have been described in only two cases (23,24,25,26).…”

Section: Introductionmentioning

confidence: 99%

Multiple aberrant hormone receptors in Cushing's syndrome

Ghorayeb

Bourdeau

Lacroix

2015

European Journal of Endocrinology

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Section: Introductionmentioning

confidence: 99%

Multiple aberrant hormone receptors in Cushing's syndrome

Ghorayeb

Bourdeau

Lacroix

2015

European Journal of Endocrinology

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“…2A). Mutation in MC2R is a rare event (21), described in two reports only (22,23). In the first one, a patient presenting with episodic cortisol excess and PBMAH harbored the germline mutation F278C leading in vitro to an increase of the accumulation of cAMP and the activation of the PKA after stimulation by ACTH (22) (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…2B). The second one concerns a patient carrying two pathogenic variants in the same allele but without PBMAH (23).…”

Section: Introductionmentioning

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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“…Hypersensitivity to ACTH, secondary to mutations of ACTH receptor MC2R, was also described in an isolated case of bilateral adrenal hyperplasia. In this particular case, the association of 2 mutations (responsible for loss of ligand binding and responsiveness) on the same allele of MC2R resulted in significant elevation in its constitutive activity and subsequent autonomous cortisol secretion (Swords et al 2004). The last actor of cAMP/PKA pathway involved in PBMAH is the alphasubunit of Gs protein (encoded by GNAS1 gene) in the context of McCune-Albright syndrome (Fragoso et al 2003).…”

Section: Primary Bilateral Macronodular Adrenal Hyperplasia (Pbmah)mentioning

confidence: 93%

Genetics of tumors of the adrenal cortex

Bonnet-Serrano

Bertherat

2018

Endocrine-Related Cancer

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This review describes the molecular alterations observed in the various types of tumors of the adrenal cortex, excluding Conn adenomas, especially the alterations identified by genomic approaches these last five years. Two main forms of bilateral adrenocortical tumors can be distinguished according to size and aspect of the nodules: primary pigmented nodular adrenal disease (PPNAD), which can be sporadic or part of Carney complex and primary bilateral macro nodular adrenal hyperplasia (PBMAH). The bilateral nature of the tumors suggests the existence of an underlying genetic predisposition. PPNAD and Carney complex are mainly due to germline-inactivating mutations of PRKAR1A, coding for a regulatory subunit of PKA, whereas PBMAH genetic seems more complex. However, genome-wide approaches allowed the identification of a new tumor suppressor gene, ARMC5, whose germline alteration could be responsible for at least 25% of PBMAH cases. Unilateral adrenocortical tumors are more frequent, mostly adenomas. The Wnt/beta-catenin pathway can be activated in both benign and malignant tumors by CTNNB1 mutations and by ZNRF3 inactivation in adrenal cancer (ACC). Some other signaling pathways are more specific of the tumor dignity. Thus, somatic mutations of cAMP/PKA pathway genes, mainly PRKACA, coding for the catalytic alpha-subunit of PKA, are found in cortisol-secreting adenomas, whereas IGF-II overexpression and alterations of p53 signaling pathway are observed in ACC. Genomewide approaches including transcriptome, SNP, methylome and miRome analysis have identified new genetic and epigenetic alterations and the further clustering of ACC in subgroups associated with different prognosis, allowing the development of new prognosis markers.

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Constitutive activation of the human ACTH receptor resulting from a synergistic interaction between two naturally occurring missense mutations in the MC2R gene

Cited by 56 publications

References 22 publications

Multiple aberrant hormone receptors in Cushing's syndrome

Multiple aberrant hormone receptors in Cushing's syndrome

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

Genetics of tumors of the adrenal cortex

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