American Journal of Medical Genetics Part A 2015-09-01

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

Karen W Gripp, Katia Sol-Church, Patroula Smpokou, Gail E Graham, David A Stevenson, Heather Hanson, David H Viskochil, Laura C Baker, Bridget Russo, Nick Gardner, Deborah L Stabley, Verena Kolbe, Georg Rosenberger

文献索引：Am. J. Med. Genet. A 167A , 2085-97, (2015)

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摘要

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. Panel testing for rasopathies identified a novel HRAS mutation (c.179G>A; p.Gly60Asp) in three individuals with attenuated features of Costello syndrome. De novo paternal origin occurred in two, transmission from a heterozygous mother in the third. Individuals showed subtle facial features; curly hair and relative macrocephaly were seen in three; atrial tachycardia and learning difficulties in two, and pulmonic valve dysplasia and mildly thickened left ventricle in one. None had severe failure to thrive, intellectual disability or cancer, underscoring the need to consider HRAS mutations in individuals with an unspecific rasopathy phenotype. Functional studies revealed strongly increased HRAS(Gly60Asp) binding to RAF1, but not to other signaling effectors. Hyperactivation of the MAPK downstream signaling pathways was absent. Our results indicate that an increase in the proportion of activated RAS downstream signaling components does not entirely explain the molecular basis of CS. We conclude that the phenotypic variability in CS recapitulates variable qualities of molecular dysfunction.© 2015 Wiley Periodicals, Inc.