MEN1, MEN4, and Carney Complex: Pathology and Molecular Genetics

Abstract

Pituitary adenomas are a common feature of a subset of endocrine neoplasia syndromes, which have otherwise highly variable disease manifestations. We provide here a review of the clinical features and human molecular genetics of multiple endocrine neoplasia (MEN) type 1 and 4 (MEN1 and MEN4, respectively) and Carney complex (CNC). MEN1, MEN4, and CNC are hereditary autosomal dominant syndromes that can present with pituitary adenomas. MEN1 is caused by inactivating mutations in the MEN1 gene, whose product menin is involved in multiple intracellular pathways contributing to transcriptional control and cell proliferation. MEN1 clinical features include primary hyperparathyroidism, pancreatic neuroendocrine tumours and prolactinomas as well as other pituitary adenomas. A subset of patients with pituitary adenomas and other MEN1 features have mutations in the CDKN1B gene; their disease has been called MEN4. Inactivating mutations in the type 1α regulatory subunit of protein kinase A (PKA; the PRKAR1A gene), that lead to dysregulation and activation of the PKA pathway, are the main genetic cause of CNC, which is clinically characterised by primary pigmented nodular adrenocortical disease, spotty skin pigmentation (lentigines), cardiac and other myxomas and acromegaly due to somatotropinomas or somatotrope hyperplasia.

Figure 1

Interacting partners of menin. Menin interacts with transcription factors including nuclear factor-κB (NF-κB), JunD, β-catenin, activator protein-1 (AP-1), mothers against decapentaplegic (SMAD) family members and oestrogen receptor α (Erα); with proteins regulating chromatin structure including histone deacetylases (HDACs) and the histone methyltransferases KMT2A and KMT2B; with cytoskeletal proteins such as vimentin, with cytoplasmic cell signalling mediators including forkhead box protein O1 (FoxO1) and Akt1/protein kinase B (PKB); and with DNA repair proteins including Fanconi anaemia group D2 protein (FANCD2).

Figure 2

The PKA pathway. A. Ligand activation of the G-protein coupled receptor (GPCR) leads to activation of the stimulatory G protein (G_s) and its α-subunit; this is followed by activation of adenylyl cyclase (AC). AC converts ATP into cAMP. In the basal state, PKA consists of two regulatory subunits (R) bound to two catalytic subunits (C). cAMP-binding to R causes dissociation from C, which is now free to act as a serine/threonine kinase. It can activate cAMP-responsive element binding protein (CREB) by phosphorylation, which mediates transcription of genes with cAMP-responsive element (CRE)-containing promoters. The PKA pathway contributes to the control of cell proliferation and differentiation, metabolism and hormone secretion. The phosphodiesterases (PDEs) hydrolyse cAMP, thereby reducing PKA pathway activity. B. In Carney complex, R1α levels are reduced, leading to increased PKA activation, reduced transforming growth factor β (TGFβ)-mediated apoptosis, increased mitogen activated protein kinase (MAPK)-dependent proliferation and a stimulated Wnt signalling pathway.

Figure 2

The PKA pathway. A. Ligand activation of the G-protein coupled receptor (GPCR) leads to activation of the stimulatory G protein (G_s) and its α-subunit; this is followed by activation of adenylyl cyclase (AC). AC converts ATP into cAMP. In the basal state, PKA consists of two regulatory subunits (R) bound to two catalytic subunits (C). cAMP-binding to R causes dissociation from C, which is now free to act as a serine/threonine kinase. It can activate cAMP-responsive element binding protein (CREB) by phosphorylation, which mediates transcription of genes with cAMP-responsive element (CRE)-containing promoters. The PKA pathway contributes to the control of cell proliferation and differentiation, metabolism and hormone secretion. The phosphodiesterases (PDEs) hydrolyse cAMP, thereby reducing PKA pathway activity. B. In Carney complex, R1α levels are reduced, leading to increased PKA activation, reduced transforming growth factor β (TGFβ)-mediated apoptosis, increased mitogen activated protein kinase (MAPK)-dependent proliferation and a stimulated Wnt signalling pathway.