Gain‐of‐function Mutations in Human Genetic Disorders


Gain‐of‐function (activating) mutations alter the amino acid sequence of gene protein products, generating proteins that have increased constitutive activity even in the absence of physiological activators or that are insensitive to negative regulation. Many of these mutations affect signaling molecules, leading to disorders resulting from constitutive activation of hormonal and other signaling pathways.

Keywords: activating mutations; guanine nucleotide regulatory protein; hormone receptors; signal transduction; McCune–albright syndrome

Figure 1.

Effect of stimulatory G protein‐α (Gsα) mutations on the guanosine triphosphatase (GTPase) cycle. The inactive Gs heterotrimer consists of guanosine diphosphate (GDP)‐bound Gsα associated with βγ dimers. Ligand‐bound G protein‐coupled receptors (GPCRs) promote GDP release. Binding of ambient GTP to Gsα changes its conformation, resulting in dissociation from βγ and activation of its effectors (adenylyl cyclase, Ca2+ channels and Src). Gsα (like all G protein α‐subunits) has an intrinsic GTPase activity that hydrolyzes bound GTP to GDP, which deactivates the G protein. Mutation of Arg201 or Gln227 inhibits the GTPase activity, producing a constitutively activated form of Gsα that remains in the active GTP‐bound state for a long period of time. cAMP: cyclic adenosine triphosphate. (Adapted from Weinstein et al..)



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Further Reading

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Weinstein, Lee S(Jan 2006) Gain‐of‐function Mutations in Human Genetic Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1038/npg.els.0005491]