PDE11A missense variants R804H and R867G were frequent in patients with adrenocortical tumors compared to 745 controls and significantly affected enzymatic function in vitro.
Observational (n=745)
Are PDE11A sequence variants associated with adrenocortical tumors and altered enzymatic function?
PDE11A missense mutations that affect enzymatic activity are present in the general population and may be associated with a wider spectrum of adrenal pathology, including in asymptomatic individuals.
Several types of adrenocortical tumors that lead to Cushing syndrome may be caused by aberrant cyclic AMP (cAMP) signaling. We recently identified patients with micronodular adrenocortical hyperplasia who were carriers of inactivating mutations in the 2q-located phosphodiesterase 11A (PDE11A) gene. We now studied the frequency of two missense substitutions, R804H and R867G, in conserved regions of the enzyme in several sets of normal controls, including 745 individuals enrolled in a longitudinal cohort study, the New York Cancer Project. In the latter, we also screened for the presence of the previously identified PDE11A nonsense mutations. R804H and R867G were frequent among patients with adrenocortical tumors; although statistical significance was not reached, these variants affected significantly enzymatic function in vitro with variable increases in cAMP and/or cyclic guanosine 3',5'-monophosphate levels in HeLa and HEK293 cells. Adrenocortical tissues carrying the R804H mutation showed 2q allelic losses and higher cyclic nucleotide levels and cAMP-responsive element binding protein phosphorylation. We conclude that missense mutations of the PDE11A gene that affect enzymatic activity in vitro are present in the general population; protein-truncating PDE11A mutations may also contribute to a predisposition to other tumors, in addition to their association with adrenocortical hyperplasia. We speculate that PDE11A genetic defects may be associated with adrenal pathology in a wider than previously suspected clinical spectrum that includes asymptomatic individuals.
Horvath et al. (Fri,) conducted a observational in Adrenocortical tumors (n=745). PDE11A sequence variants (R804H and R867G) vs. Normal controls was evaluated on Frequency of PDE11A missense substitutions and in vitro enzymatic function. PDE11A missense variants R804H and R867G were frequent in patients with adrenocortical tumors compared to 745 controls and significantly affected enzymatic function in vitro.