Attenuated phenotype of Costello syndrome and early death in a patient with an HRAS Mutation (c.179G>T; p.Gly60Val) affecting signalling dynamics
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Attenuated phenotype of Costello syndrome and early death in a patient with an HRAS Mutation (c.179G>T; p.Gly60Val) affecting signalling dynamics. / Gripp, Karen W; Kolbe, Verena; Brandenstein, Laura Isabel; Rosenberger, Georg.
In: CLIN GENET, Vol. 92, No. 3, 31.01.2017, p. 332-337.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Attenuated phenotype of Costello syndrome and early death in a patient with an HRAS Mutation (c.179G>T; p.Gly60Val) affecting signalling dynamics
AU - Gripp, Karen W
AU - Kolbe, Verena
AU - Brandenstein, Laura Isabel
AU - Rosenberger, Georg
N1 - This article is protected by copyright. All rights reserved.
PY - 2017/1/31
Y1 - 2017/1/31
N2 - 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. Though 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, PLCE1, and RALGDS. In contrast, interaction with effector RAF1 and regulator NF1 GAP was enhanced. Importantly, expression of HRAS p.Gly60Val in HEK293 cells reduced growth factor sensitivity leading to damped RAF-MAPK and PI3K-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.
AB - 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. Though 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, PLCE1, and RALGDS. In contrast, interaction with effector RAF1 and regulator NF1 GAP was enhanced. Importantly, expression of HRAS p.Gly60Val in HEK293 cells reduced growth factor sensitivity leading to damped RAF-MAPK and PI3K-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.
U2 - 10.1111/cge.12980
DO - 10.1111/cge.12980
M3 - SCORING: Journal article
C2 - 28139825
VL - 92
SP - 332
EP - 337
JO - CLIN GENET
JF - CLIN GENET
SN - 0009-9163
IS - 3
ER -