PRKAR1A and the evolution of pituitary tumors

Abstract

Carney Complex (CNC) is an inherited tumor predisposition associated with pituitary tumors, including GH-producing pituitary adenomas and rare reports of prolactinomas. This disease is caused by mutations in PRKAR1A, which encodes the type 1A regulatory subunit of the cAMP-dependent Protein Kinase, PKA. Loss of PRKAR1A causes enhanced PKA signaling, which leads to pituitary tumorigenesis. Mutations in the gene have not been detected in sporadic pituitary tumors, but there is some data to suggest that non-genomic mechanisms may cause loss of protein expression. Unlike CNC patients, mice heterozygous for Prkar1a mutations do not develop pituitary tumors, although complete knockout of the gene in the Pit1 lineage of the pituitary produces GH-secreting pituitary adenomas. These data indicate that complete loss of Prkar1a/PRKAR1A is able to cause pituitary tumors in mice and men. The pattern of tumors is likely related to the signaling pathways employed in specific pituitary cell types.

Familial Pituitary Adenomas: An Overview

“…Tissue-speci fi c ablation of PRKAR1A gene in mice, however, induces gradual development of pituitary tumours with biochemical features, quite similar to CNC-related acromegaly in humans, e.g. GH hypersecretion with slow progression from hyperplasia to adenoma (Kirschner 2010 ) .…”

“…Less common endocrine presentations include large cell calcifying sertoli cell tumours (LCCSCTs) and benign or malignant thyroid nodules (Boikos and Stratakis 2007 ) . Pituitary adenomas occur with an incidence of 10-12% of CNC patients and usually cause acromegaly or gigantism depending on the age of onset but at least one family with prolactinomas has also been reported (Kirschner 2010 ) . A distinguishing feature of GH-secreting tumours in CNC is multifocal hyperplasia of somatomammotrope cells amidst normal pituitary tissue.…”

“…In 1985Carney et al ( 1986 described a new multiple tumour syndrome (CNC) that presented infrequently with familial acromegaly. Genetic research has linked almost 70% of cases with Carney complex to mutations in the gene for type A regulatory subunit of protein kinase A (PRKAR1A) (Kirschner 2010 ) . By the end of 1990s, however, signi fi cant numbers of patients had accumulated who had familial pituitary tumours without mutations in either MEN1 or PRKAR1A genes.…”

A Novel Inherited Mutation in PRKAR1A Abrogates PreRNA Splicing in a Carney Complex Family

“…Carney complex (CNC) is a rare autosomal dominant inherited disease characterized by spotty skin pigmentation, cardiac and cutaneous myxomas, and endocrine overactivity [1][2][3][4][5] . The syndrome was first described in 1985 by Carney et al 6 In this communication, we report a Chinese CNC family characterized by cardiac and cutaneous myxomas, skin pigmentation, and multiple hypoechoic thyroid nodules.…”

Pituitary adenomas in the framework of hereditary syndromes

“…Аденомы гипофиза при CNC в подавляющем большинстве случаев СТГ или СТГ/ПРЛ-секретирующие, около 2 / 3 пациентов с CNC имеют «мягкую» гиперпролактинемию (менее 100 нг/мл), но было описано несколько случаев ис-тинных пролактином [29]. В гипофизе гормон ро-ста-рилизинг гормон (ГР-РГ) стимулирует синтез и высвобождение СТГ посредством системы цАМФ/ ПКА.…”