Heterotrimeric G proteins couple receptors for diverse extracellular signals to effector enzymes or ion channels. Each G protein comprises a specific α-subunit and a tightly bound βγ dimer. Several human disorders that result from genetic G-protein abnormalities involve the imprinted GNAS gene, which encodes G_sα, the ubiquitously expressed α-subunit that couples receptors to adenylyl cyclase and cAMP generation. Loss-of-function and gain-of-function mutations, in addition to imprinting defects, of this gene lead to diverse clinical phenotypes. Mutations of GNAT1 and GNAT2, which encode the retinal G proteins (transducins), are rare causes of specific congenital visual defects. Common polymorphisms of the GNAS and GNB3 (which encodes Gβ₃) genes have been associated with multigenic disorders (e.g. hypertension and metabolic syndrome). To date, no other G proteins have been implicated directly in human disease.