Genomic and sequence variants of protein kinase A regulatory subunit type 1β (PRKAR1B) in patients with adrenocortical disease and Cushing syndrome

PURPOSE: Protein kinase A (PKA) subunit defects (in PRKAR1A and PRKACA) are known to contribute to adrenal tumor pathogenesis. We studied the PRKAR1B gene for any genetic changes in bilateral adrenocortical hyperplasia (BAH) and cortisol-producing adrenal adenomas (CPA). METHODS: Exome sequencing and PRKAR1B copy number variant (CNV) analysis were performed in 74 patients with BAH and 21 with CPA. PKA activity was studied in tumors with defects; sequence variants were investigated in vitro. RESULTS: Three PRKAR1B germline variants (p.I40V, p.A67V, p.A300T) were identified among 74 patients with BAH. PRKAR1B copy number gains (CNG) were found in 3 of 21 CPAs, one in a tumor carrying a somatic PRKACA “hot-spot” pathogenic variant p.L206R. CPAs bearing PRKAR1B CNGs showed higher PRKAR1B mRNA levels and reduced PKA activity. Baseline PKA activity was also decreased for p.A67V and p.A300T in vitro, and mutant PRKAR1β bound PRKACα in FRET recordings of co-transfected HEK293 cells stronger than normal. CONCLUSION: PRKAR1B is yet another PKA subunit that may potentially contribute to adrenal tumor formation. Its involvement in adrenocortical disease may be different from that of other subunits, because PRKAR1B variants and PRKAR1B CNG were associated with decreased (rather than increased) overall PKA activity in vitro.