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Title: Mutation analysis in Costello syndrome: functional and structural characterization of the HRAS p.Lys117Arg mutation
Authors: Denayer, Ellen
Parret, Annabel
Chmara, Magdalena
Schubbert, Suzanne
Vogels, Annick
Devriendt, Koenraad
Fryns, Jean-Pierre
Rybin, Vladimir
de Ravel, Thomy
Shannon, Kevin
Cools, Jan
Scheffzek, Klaus
Legius, Eric # ×
Issue Date: Feb-2008
Publisher: John Wiley & Sons, Inc.
Series Title: Human Mutation vol:29 issue:2 pages:232-239
Abstract: Costello syndrome is a mental retardation syndrome characterized by high birth weight, postnatal growth retardation, coarse face, loose skin, cardiovascular problems, and tumor predisposition. De novo heterozygous missense mutations in HRAS codon 12 and 13 disturbing the intrinsic GTP hydrolysis cause Costello syndrome. We report a patient with typical Costello syndrome and a novel heterozygous missense mutation in codon 117 (c.350A>G, p.Lys117Arg) of the HRAS gene, resulting in constitutive activation of the RAS/MAPK pathway similar to the typical p.Gly12Ser and p.Gly12Ala mutations. Recombinant HRAS p.Lys117Arg demonstrates normal intrinsic GTP hydrolysis and responsiveness to GTPase-activating proteins, but the nucleotide dissociation rate is increased 80-fold. Consistent with the biochemical data, the crystal structure of the p.Lys117Arg mutant indicates an altered interaction pattern of the side chain that is associated with unfavorable nucleotide binding properties. Together, these data show that a RAS mutation that only perturbs guanine nucleotide binding has similar functional consequences as mutations that impair GTP hydrolysis and causes human disease.
URI: 
ISSN: 1059-7794
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Genetics Section (-)
Department of Human Genetics - miscellaneous
Clinical Genetics Section (-)
Laboratory for Neurofibromatosis Research
× corresponding author
# (joint) last author

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