Gain‐of‐function Mutations in Human Genetic Disorders

Lee S Weinstein, National Institutes of Health, Bethesda, Maryland, USA

Published online: January 2006

DOI: 10.1038/npg.els.0005491

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- (Gs) mutations on the guanosine triphosphatase (GTPase) cycle. The inactive Gs heterotrimer consists of guanosine diphosphate (GDP)-bound Gs associated with dimers. Ligand-bound G protein-coupled receptors (GPCRs) promote GDP release. Binding of ambient GTP to Gs changes its conformation, resulting in dissociation from and activation of its effectors (adenylyl cyclase,  Ca2+ channels and Src). Gs (like all G protein -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 Gs that remains in the active GTP-bound state for a long period of time. cAMP: cyclic adenosine triphosphate. (Adapted from Weinstein et al. (2001).)
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Related Sub-Topics:

Membrane Proteins | Signal Transduction | Specific Genetic Disorders | Mutational Mechanisms of Genetic Disease | Cancer Genetics
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Article Title: Gain‐of‐function Mutations in Human Genetic Disorders
 
How to Cite close
Weinstein, Lee S(Jan 2006) Gain‐of‐function Mutations in Human Genetic Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0005491]