title: Attenuated phenotype of Costello syndrome and early death in a patient with an HRAS mutation (c.179G>T; p.Gly60Val) affecting signalling dynamics.
abstract: Costello syndrome (CS) is caused by heterozygous germline HRAS mutations. Most patients share the HRAS mutation c.34G>A (p.Gly12Ser) associated with the typical, relatively homogeneous phenotype. Rarer mutations occurred in individuals with an attenuated phenotype. Although many disease-associated HRAS alterations trigger constitutive activation of HRAS-dependent signalling pathways, additional pathological consequences exist. An infant with failure-to-thrive and hypertrophic cardiomyopathy had a novel de novo HRAS mutation (c.179G>T; p.Gly60Val). He showed subtle dysmorphic findings consistent with attenuated CS and died from presumed cardiac cause. Functional studies revealed that amino acid change p.Gly60Val impairs HRAS binding to effectors PIK3CA, phospholipase C1, and RAL guanine nucleotide dissociation stimulator. In contrast, interaction with effector rapidly accelerated fibrosarcoma (RAF) and regulator NF1 GTPase-activating protein was enhanced. Importantly, expression of HRAS p.Gly60Val in HEK293 cells reduced growth factor sensitivity leading to damped RAF-MAPK and phosphoinositide 3-kinases-AKT signalling response. Our data support the idea that a variable range of dysregulated HRAS-dependent signalling dynamics, rather than static activation of HRAS-dependent signal flow, may underlie the phenotypic variability in CS.
authors.affiliation: Division of Medical Genetics, A. I. duPont Hospital for Children/Nemours, Wilmington, Delaware.
authors.forename: K W
authors.identifier: http://orcid.org/0000-0001-8200-1733
authors.initials: KW
authors.lastname: Gripp
authors.affiliation: Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Kolbe
authors.affiliation: Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: L I
authors.initials: LI
authors.lastname: Brandenstein
authors.affiliation: Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Rosenberger
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D001344:Autopsy; D002460:Cell Line; D056685:Costello Syndrome / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D017809:Fatal Outcome; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010641:Phenotype; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Costello syndrome; HRAS; Ras/MAPK; rasopathy