Disease relevance of CNC

• Carney complex (CNC) is a familial multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac and cutaneous myxomas, and endocrine tumors [1].
• 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 [2].
• So far, half of the patients with CNC have germline inactivating mutations in the PRKAR1A gene; in their pituitary tumors, the normal allele of the PRKAR1A gene is lost [3].
• These data provide evidence for a PRKAR1A-induced somatomammotroph hyperpasia in the pituitary tissue of CNC patients; hyperplasia, in turn may lead to additional genetic changes at the somatic level, which then cause the formation of adenomas in some, but not all, patients [3].
• Carney complex, a familial multiple neoplasia and lentiginosis syndrome. Analysis of 11 kindreds and linkage to the short arm of chromosome 2 [4].

Psychiatry related information on CNC

• It also harbors the genes for several genetic disorders, including Type I hereditary nonpolyposis colorectal cancer (HNPCC), familial male precocious puberty (FMPP), Carney complex (CNC), Doyne's honeycomb retinal dystrophy (DHRD), and one form of familial dyslexia (DYX-3) [5].
• These genes are deleted in individuals with TI deletion and are implicated in compulsive behavior and lower intellectual ability in individuals with TI versus TII [6].
• Adaptive behavior, obsessive-compulsive behaviors, reading, math, and visual-motor integration assessments were generally poorer in individuals with Prader-Willi syndrome and the TI deletion compared with subjects with Prader-Willi syndrome with the TII deletion or uniparental maternal disomy 15 [7].

High impact information on CNC

• In CNC families mapping to 17q, we detected loss of heterozygosity (LOH) in the vicinity of the gene (PRKAR1A) encoding protein kinase A regulatory subunit 1-alpha (RIalpha), including a polymorphic site within its 5' region [8].
• Although cardiac tumorigenesis may require a second somatic mutation, DNA and protein analyses of an atrial myxoma resected from a Carney complex patient with a PRKAR1alpha deletion revealed that the myxoma cells retain both the wild-type and the mutant PRKAR1alpha alleles and that wild-type R1alpha protein is stably expressed [9].
• Our linkage analysis mapped a Carney complex gene defect to chromosome 17q24 [9].
• Furthermore, we show that PRKAR1alpha frameshift mutations in three unrelated families result in haploinsufficiency of R1alpha and cause Carney complex [9].
• The flanking markers CA7 and D2S378 defined a region of approximately 6.4 cM that is likely to contain the gene(s) associated with Carney complex [4].

Chemical compound and disease context of CNC

• PRKAR1A, which codes for the RIalpha regulatory subunit of cyclic AMP-dependent protein kinase A (PKA) on 17q23-24, was recently reported to contain inactivating mutations in some Carney complex families, which involved GH-secreting adenomas in about 10% [10].
• A six month mitotane course induced sustained correction of hypercortisolism in a young woman with PPNAD and Carney complex [11].
• TII cells contain ENaC and cystic fibrosis transmembrane regulator, but few pimozide-sensitive cation channels [12].
• Two particularly severe dwarfisms, thanatophoric dysplasia type II (TDII) and severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), are associated with glutamic acid (E) and methionine (M) substitutions at the K650 residue in the kinase domain [13].

Biological context of CNC

• We conclude that cytogenetic changes of the 2p16 chromosomal region that harbours the CNC2 locus are frequently observed in tumours from CNC patients, including those with germline, inactivating PRKAR1A mutations [14].
• To define more precisely the 2p amplicon in these and other tumours, we completed the genomic mapping of the CNC2 region, and analysed 46 tumour samples from CNC patients with and without PRKAR1A mutations by fluorescence in situ hybridisation (FISH) using bacterial artificial chromosomes (BACs) [14].
• Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the carney complex [15].
• Chromosome 2 (2p16) abnormalities in Carney complex tumours [14].
• Histochemistry of tissues from CNC patients is indicative of autophagic deficiency and this led us to investigate the relationship between RIalpha and mammalian autophagy [16].

Anatomical context of CNC

• We conclude that unregulated PKA activity in male meiotic or postmeiotic germ cells leads to structural defects in mature sperm and results in reduced fertility in mice and humans, contributing to the strikingly reduced transmission of PRKAR1A inactivating mutations by male patients with CNC [1].
• OBJECTIVE: Carney complex (CNC) is an autosomal dominant multiple neoplasia syndrome featuring cardiac, endocrine, cutaneous and neural tumours, as well as a variety of pigmented lesions of the skin and mucosa [17].
• Heterozygous loss of function mutations in human PKAR1A gene (PRKAR1A) have been identified in patients with Carney complex (CNC), an autosomal dominant familial multiple neoplasia syndrome displaying different endocrine tumors, including adrenocortical tumors, GH-secreting pituitary tumors and thyroid adenomas [18].
• Pathology and molecular genetics of the pituitary gland in patients with the 'complex of spotty skin pigmentation, myxomas, endocrine overactivity and schwannomas' (Carney complex) [19].
• Carney complex is inherited as an autosomal dominant trait and may simultaneously involve multiple endocrine glands, as in the classic multiple endocrine neoplasia syndromes 1 and 2 [20].

Associations of CNC with chemical compounds

• PPNAD and/or CNC patients with and without mutations leading to protein kinase A activation demonstrated in vitro and/or in vivo paradoxical dexamethasone responses and GR expression, indicating that PRKAR1A alterations are not necessary for these phenomena [21].
• Molecular analysis of the cyclic AMP-dependent protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene in patients with Carney complex and primary pigmented nodular adrenocortical disease (PPNAD) reveals novel mutations and clues for pathophysiology: augmented PKA signaling is associated with adrenal tumorigenesis in PPNAD [22].
• These tissues are also targets of Carney complex (CNC), a multiple neoplasia syndrome caused by germline inactivating PRKAR1A mutations (PRKAR1A-mut) and associated with primary pigmented nodular adrenocortical disease (PPNAD) and increased steroid synthesis [23].
• Substitution of all 4 non-activation loop tyrosine residues significantly attenuated, but did not abolish, TDII transforming activity [24].
• Furthermore, following TDII transfection, signal transducer and activator of transcription 1 (STAT1) is phosphorylated in the absence of FGFR3 ligand and brefeldin A does not inhibit its activation [25].

Regulatory relationships of CNC

• We have shown previously that patients with the autosomal dominant tumor predisposition Carney complex carry inactivating mutations in the PRKAR1A gene, which encodes the type 1A regulatory subunit of protein kinase A (PKA), the cyclic AMP-dependent protein kinase [26].
• The congenital gene defects of Carney complex or of Peutz-Jeghers syndrome might trigger a cascade of intracellular events that leads to overexpression of aromatase in Sertoli cells, favoring the development of a LCCSCT [27].

Other interactions of CNC

• Hereditary cases of growth hormone (GH)-secreting tumors have been classified into three clinical entities: the multiple endocrine neoplasia type 1 (MEN1) syndrome, the Carney complex (CNC) and the isolated familial somatotropinomas (IFS) [28].
• Mutations in the exons or intron-exon boundaries of PRKAR1B (7p22, closely related to PRKAR1A, which is mutated in Carney complex) have been excluded in this family [29].
• Further genetic studies in human beings have highlighted novel variant phenotypes, such as congenital contractures, which are potentially associated with Carney complex, and have identified alternative genetic pathways to cardiac tumorigenesis, including mutation of the MYH8 gene that encodes perinatal myosin [30].
• Synaptophysin immunoreactivity in primary pigmented nodular adrenocortical disease: neuroendocrine properties of tumors associated with Carney complex [31].
• BACKGROUND: Familial cardiac myxomas occur in the hereditary syndrome Carney complex [32].

Analytical, diagnostic and therapeutic context of CNC

• In the present study, 17 odontogenic myxomas from patients without CNC were screened for PRKAR1A mutations and PRKAR1A protein expression by immunohistochemistry (IHC) [33].
• Animal models of the disease have been recently developed; they reproduced some of the stigmata of Carney complex syndrome but not all [34].
• Endocrine evaluation showed that this patient's symptoms fulfilled the diagnostic criteria of Carney complex, with lentiginosis, multiple breast ductal adenomas, multiple hypoechoic nodules on thyroid ultrasonography, and a 4 x 5-cm asymptomatic atrial cardiac myxoma, which was removed 15 days after the neurosurgery [35].
• An implant-supported prosthesis with a CNC-milled framework for the rehabilitation of the edentulous jaw [36].
• These new lists and the ten original CNC lists (Peterson and Lehiste, 1962) were used during the feasibility study of the Nucleus Research Platform 8 Cochlear Implant System (Holden et al, 2004) [37].

References