PRKAR1A

Molecular characteristics

The function of PRKAR1A
PRKAR1A encodes the type I alpha regulatory subunit of the protein kinase A (PKA) enzyme. PKA is a heterotetramer consisting of two regulatory and two catalytic subunits. G protein-coupled receptor activation leads to the production of cAMP which binds to the regulatory subunits of PKA and allows dissociation from the catalytic subunits, subsequently activating the enzyme. PKA phosphorylates down-stream cAMP response-binding protein (CREB), which initiate several biological processes including cell proliferation.

Pathophysiological mechanisms and the types of pathogenic variants
Disease-causing variants in PRKAR1A lead to a loss of function for the regulatory subunit and constitutive activation of PKA. Tumor formation in patients with CNC is a result of uncontrolled PKA activity.

Nonsense or insertion/ deletion pathogenic variants are most common, although missense, splice site variants, and whole gene deletions have been reported and can be found in the following database https://prkar1a.nichd.nih.gov/hmdb/intro.html. The majority are private, with only three disease-causing variants reported across three unrelated families (c.82C>T, c.491_492delTG, and c.709-2_09-7 delATTTTT). Most commonly, pathogenic variants produce a truncated and/or defective mRNA which is degraded by nonsense-mediated decay prior to translation to a protein. Ultimately, the result is PRKAR1A haploinsufficiency and a 50% reduction in type I alpha regulatory subunit production. In rare cases, missense variants may be translated, where in vitro experiments have shown pathogenicity as a result of inadequate response or binding to cAMP in addition to decreased protein production. Interestingly, these pathogenic variants have been associated with more severe disease, although the exact mechanism of why this occurs remains unknown.

Genetic testing
Pathogenic variants are detected using Sanger sequencing analysis of the PRKAR1A gene. If no pathogenic variants are found, copy number variant and gene-targeted deletion analysis should be performed to detect exon or whole-gene deletions or duplications which may not have been detected by Sanger sequencing. After ruling out pathogenic PRKAR1A variants, other genetic causes of CNC can be explored (i.e. PRKACA, PRKACB). Additionally, genetic linkage analysis has shown a second locus for CNC at chromosome 2p16, although the gene involved remains unknown.