[Mutation of G proteins].

Guanine nucleotide-binding proteins (G proteins) function as transducers of information across the cell membrane by coupling receptors to effectors. A large number of G protein-linked receptors funnel extracellular signals as diverse as hormones, growth factors, neurotransmitters, and primary sensory stimuli through a set of G proteins to a small number of second-messenger systems. The G proteins act as molecular switches with an "on" and "off" state governed by a GTPase cycle. By virtue of its high affinity and specificity for guanine nucleotide binding and its intrinsic GTPase activity, the alpha-subunit of the G protein (G alpha) plays the critical role in regulation of the effectors by their corresponding G protein. Mutations of G alpha may result in either constitutive activation or loss of expression mutations. Given the variety of functions subserved by G protein-coupled signal transduction, it is not surprising that abnormalities in G protein-coupled pathways can lead to diseases with manifestations as dissimilar as blindness, hormone resistance, precocious puberty and neoplasia. For a given defect in a G protein-coupled pathway, the extent of the manifestations will also be determined by the cellular distribution of the affected component. Defects in components expressed exclusively in a single cell type will cause more a focal disorder than defects in a widely expressed component, particularly in germline mutations (e.g., Albright's hereditary osteodystrophy), whereas somatic mutations of genes encoding even an ubiquitously expressed component can cause focal disease when the somatic mutation itself is focal (e.g., McCune-Albright syndrome).