Mutations and polymorphisms in the gene encoding regulatory subunit type 1-alpha of protein kinase A (PRKAR1A): an...

Area of Science:

• Genetics
• Molecular Biology
• Oncology

Background:

• PRKAR1A mutations are the primary cause of Carney complex (CNC), a syndrome involving multiple tumors and lentigines.
• Most known pathogenic PRKAR1A variants lead to RIalpha haploinsufficiency via nonsense-mediated mRNA decay (NMD), activating cAMP signaling.
• CNC can also result from altered RIalpha protein expression, not just haploinsufficiency.

Purpose of the Study:

• To provide a comprehensive analysis of all known PRKAR1A sequence variations.
• To discuss the molecular context and clinical phenotypes associated with these PRKAR1A variations.
• To characterize novel mutation types, including those escaping NMD.

Main Methods:

• Systematic review and analysis of reported PRKAR1A sequence variations.
• In silico and experimental analysis of mutation impact on protein expression and function.
• Correlation of genotype with clinical phenotype in Carney complex patients.

Main Results:

• Over 117 pathogenic PRKAR1A variants have been identified, with a detection rate exceeding 60% in CNC patients.
• Identified novel frame-shift mutations in the 3' coding sequence that escape NMD, leading to altered RIalpha protein.
• Demonstrated that both RIalpha haploinsufficiency and expression of altered RIalpha protein can cause CNC.

Conclusions:

• PRKAR1A sequence variations are diverse, encompassing both loss-of-function and altered-function mutations.
• A comprehensive understanding of PRKAR1A variants is crucial for diagnosing and managing Carney complex.
• Further research into PRKAR1A mutation-negative CNC cases is warranted due to phenotypic heterogeneity.