title: Mutation analysis in Costello syndrome: functional and structural characterization of the HRAS p.Lys117Arg mutation.
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.
authors.affiliation: Department of Human Genetics, Catholic University of Leuven, Leuven, Belgium.
authors.forename: Ellen
authors.initials: E
authors.lastname: Denayer
authors.forename: Annabel
authors.initials: A
authors.lastname: Parret
authors.forename: Magdalena
authors.initials: M
authors.lastname: Chmara
authors.forename: Suzanne
authors.initials: S
authors.lastname: Schubbert
authors.forename: Annick
authors.initials: A
authors.lastname: Vogels
authors.forename: Koen
authors.initials: K
authors.lastname: Devriendt
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Frijns
authors.forename: Vladimir
authors.initials: V
authors.lastname: Rybin
authors.forename: Thomy J
authors.initials: TJ
authors.lastname: de Ravel
authors.forename: Kevin
authors.initials: K
authors.lastname: Shannon
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
authors.forename: Klaus
authors.initials: K
authors.lastname: Scheffzek
authors.forename: Eric
authors.initials: E
authors.lastname: Legius
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D001120:Arginine / Q000235:genetics*; D001483:Base Sequence; D002460:Cell Line; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D003062:Codon; D004252:DNA Mutational Analysis; D006153:Guanosine Diphosphate / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D007223:Infant; D007231:Infant, Newborn; D008239:Lysine / Q000235:genetics*; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry; D009154:Mutation / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000737:chemistry* / Q000235:genetics*; D013577:Syndrome
chemical_list: D003062:Codon; D050505:Mutant Proteins; D006153:Guanosine Diphosphate; D001120:Arginine; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D008239:Lysine