An attenuated phenotype of Costello syndrome in three unrelated individuals with a HRAS c.179G>A (p.Gly60Asp) mutation correlates with uncommon functional consequences.

ABSTRACT: Heterozygous germline mutations in the proto-oncogene HRAS cause Costello syndrome (CS), an intellectual disability condition with severe failure to thrive, cardiac abnormalities, predisposition to tumors, and neurologic abnormalities. More than 80% of 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 and less characteristic facial features. Most pathogenic HRAS alterations affect hydrolytic HRAS activity resulting in constitutive activation. "Gain-of-function" and "hyperactivation" concerning downstream pathways are widely used to explain the molecular basis and dysregulation of the RAS-MAPK pathway is the biologic mechanism shared amongst rasopathies. Pa

SUBMITTER: Gripp KW 

PROVIDER: S-EPMC4830354 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature