PRKAR1A – Carney Complex

PRKAR1A encodes the type I-α regulatory subunit of cyclic AMP-dependent protein kinase A. Heterozygous inactivating variants in PRKAR1A cause Carney complex, an autosomal dominant multiple neoplasia syndrome characterized by spotty skin pigmentation, myxomas (cardiac and cutaneous), primary pigmented nodular adrenocortical disease (PPNAD), and endocrine tumors such as GH-secreting pituitary adenomas with acromegaly (PMID:10974026).

1. Clinical Validity

Definitive: PRKAR1A loss-of-function variants have been reported in over 350 CNC patients across >80 kindreds, with multi-family segregation and consistent in vitro and in vivo functional concordance (PMID:19293268).

2. Genetic Evidence

• Inheritance: Autosomal dominant.
  
• Segregation: The novel frameshift c.597delC (p.Phe200LeufsTer6) was identified in a proband and segregated with disease in two additional affected relatives (mother, sister) (affected_relatives: 2) (PMID:18760947).
  
• Case series: PRKAR1A frameshift and nonsense variants (e.g., c.491_492del (p.Val164fs)) have been described in three unrelated families resulting in haploinsufficiency (PMID:10974026; PMID:11115848).
  
• Variant spectrum: Over 80 distinct pathogenic variants (frameshift, nonsense, splice site) predicted to trigger nonsense-mediated decay; recurrent small deletions such as c.491_492del (p.Val164fs) are noted.
  

3. Functional Evidence

• Mechanism: Haploinsufficiency of the RIα subunit leads to constitutive PKA catalytic subunit activation and paradoxical cAMP signalling.
  
• Key assays: Knockout and knock-in models replicate endocrine and myxomatous phenotypes; patient-derived cells show elevated basal and cAMP-stimulated PKA activity and loss of RIα protein (PMID:10974026; PMID:12812976).
  

4. Conflicting Evidence

No robust refuting evidence; PRKAR1A-negative CNC kindreds map to an alternative locus on 2p16, indicating genetic heterogeneity rather than contradiction of PRKAR1A association (PMID:11115848).

5. Integration & Take-Home

PRKAR1A pathogenic variants cause Carney complex via RIα haploinsufficiency and PKA hyperactivity, leading to a pleiotropic tumor phenotype. Clinical genetic testing of PRKAR1A informs diagnosis, enables cascade screening, and guides surveillance for cardiac myxoma and endocrine tumors.

References

• Molecular genetics and metabolism • 2008 • Case report of familial Carney complex due to novel frameshift mutation c.597del C (p.Phe200LeufsTer6) in PRKAR1A. PMID:18760947
• The Journal of clinical investigation • 2000 • Mutations in the protein kinase A R1alpha regulatory subunit cause familial cardiac myxomas and Carney complex. PMID:10974026
• Human molecular genetics • 2000 • Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the Carney complex. PMID:11115848
• The Journal of clinical endocrinology and metabolism • 2009 • Mutations in regulatory subunit type 1A of cyclic adenosine 5'-monophosphate-dependent protein kinase (PRKAR1A): phenotype analysis in 353 patients and 80 different genotypes. PMID:19293268
• Human molecular genetics • 2003 • Protein kinase A activity in PRKAR1A-mutant cells, and regulation of mitogen-activated protein kinases ERK1/2. PMID:12812976

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