Carney complex: pathology and molecular genetics.
Carney complex (CNC) is a unique multiple endocrine neoplasia syndrome (MIM 160980) which is characterized by unusual biochemical features (chronic hypersomatotropinemia and paradoxical responses of cortisol production to glucocorticoids) and multi-tissue involvement. The gene coding for the protein kinase A (PKA) type 1alpha regulatory subunit, PRKAR1A, had been mapped to 17q22-24, one of the genetic loci involved in CNC, and allelic analysis using probes from this chromosomal region revealed consistent changes in CNC tumors. Sequencing of the PRKAR1A gene in over 100 kindreds showed a number of mutations; in almost all cases, the sequence change was predicted to lead to a premature stop codon, and mutant mRNAs were subject to nonsense-mediated mRNA decay. In CNC cells, PKA activity assays showed increased stimulation by cAMP. Few mutations that did not lead to a premature stop codon have been described; they are also associated with increased PKA activity. PRKAR1A has been investigated in sporadic endocrine tumors; it does not appear to be mutated in pituitary adenomas, but both thyroid and adrenal neoplasms have been found to harbor somatic mutations of this gene. Animal models of the disease have been developed. CNC is the first human disease caused by mutations of one of the subunits of the PKA holoenzyme, a critical component of numerous cellular signaling systems. This has wide implications for cAMP involvement in endocrine tumorigenesis.
Boikos
Sosipatros A
SA
Section on Endocrinology and Genetics, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Md., USA.
Stratakis
Constantine A
CA
D000172:Acromegaly / Q000097:blood / Q000150:complications / Q000235:genetics* / Q000473:pathology; D000310:Adrenal Gland Neoplasms / Q000097:blood / Q000150:complications / Q000235:genetics* / Q000473:pathology; D000818:Animals; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics*; D004195:Disease Models, Animal; D013006:Growth Hormone / Q000097:blood; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D009377:Multiple Endocrine Neoplasia / Q000097:blood / Q000150:complications / Q000235:genetics* / Q000473:pathology; D009232:Myxoma / Q000097:blood / Q000150:complications / Q000235:genetics* / Q000473:pathology; D009378:Neoplasms, Multiple Primary / Q000097:blood / Q000150:complications / Q000235:genetics* / Q000473:pathology; D010859:Pigmentation Disorders / Q000097:blood / Q000150:complications / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D013577:Syndrome
D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human; D012333:RNA, Messenger; D013006:Growth Hormone; D017868:Cyclic AMP-Dependent Protein Kinases; D006854:Hydrocortisone