Characterizing intragenic suppressors of constitutively active alleles of G_s alpha (802.6)

Abstract

Constitutive activity of Gs alpha is associated with several human diseases, including McCune‐Albright Syndrome (MAS). In this genetic disorder, Arg201 is mutated to His, Cys, or Ser, resulting in inhibition of GTP hydrolysis and subsequent overactivation of adenylyl cyclase and elevated basal cAMP levels. Previous studies identified three intragenic suppressor sites that blocked the constitutive activity caused by R201H: F142, R231, and L266. These mutations did not by themselves alter the activity of Gs alpha. The intragenic suppressors were examined for their ability to block the other MAS alleles. F142S and R231C suppressed the constitutive activity of both of MAS alleles. L266N suppressed R201S, and is currently being tested for the ability to block the constitutive activity of R201C. Thus, the intragenic suppressors may be useful drug targeting sites for MAS mutations generally, not just for R201H‐caused cases of the disease. Grant Funding Source: Supported by NIH grant 1R15ED020190‐01