Mutations in G proteins are involved in several diseases, ranging from Whooping Cough and Cholera to several endocrine disorders. G protein-related diseases are characterised by either deficient or excessive G protein signal transmission, which arises through abnormal signal initiation, defective termination, or reduced levels of G proteins. Perturbation of G-protein signalling is also central to the actions of many drugs, including those used to treat asthma, hypertension and depression.
Deficient G protein signalling can arise through either reduced levels of G proteins, or through decrease signal initiation. Diseases involving a decrease in the production of G proteins include Night Blindness, where mutations in G(t) protein a subunits affect the response of rod cells to light; and Pseudohypoparathyroidism, where the genetic loss of G(s) protein a subunits results in non-responsiveness to parathyroid hormone. Other abnormalities involve decreased signal initiation through the inability of G proteins to switch to active states. For example, the symptoms of Whooping Cough (Pertussis) result from the action of a bacterial toxin, which adds ADP-ribose to the receptor-binding C-terminal tail of G(i) protein a subunits, causing a reduced responsiveness of G proteins to receptor activation.
Excessive G protein signalling can arise through either increased signal initiation, or defective signal termination. Increased signal initiation occurs in Testotoxicosis, where a mutation in the receptor for luteinizing hormone can over-stimulate G(s) proteins, resulting in the excessive production of testosterone; in addition, several cases of Essential Hypertension arise from mutations in G protein b subunits. Diseases arising from defective signal termination result from the persistent elevated activity of downstream effectors, such as in Cholera, the symptoms of which results from the action of a bacterial toxin that adds ADP-ribose to G(s) protein a subunits to prolong their activation, resulting in the stimulation of adenylyl cyclase and the subsequent secretion of salt and water leading to fatal diarrhoea. Two other diseases involve defective termination through mutations in G(s) protein a subunits, including Adenomas, in which G proteins lose their ability to hydrolyse GTP through mutation, resulting in the excessive secretion of growth hormone and the increased proliferation of somatotrophs; and McCune-Albright Syndrome, where scattered regions of skin hyper-pigmentation arise from the hyper-functioning of one or more endocrine glands.