Gripp Karen W, Sol-Church Katia, Smpokou Patroula, Graham Gail E, Stevenson David A, Hanson Heather, Viskochil David H, Baker Laura C, Russo Bridget, Gardner Nick, Stabley Deborah L, Kolbe Verena, Rosenberger Georg
Division of Medical Genetics, A. I. duPont Hospital for Children, Wilmington, Delaware.
Center for Applied Clinical Genomics, A. I. duPont Hospital for Children, Wilmington, Delaware.
Am J Med Genet A. 2015 Sep;167A(9):2085-97. doi: 10.1002/ajmg.a.37128. Epub 2015 Apr 25.
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.
原癌基因HRAS的杂合种系突变会导致科斯特洛综合征（CS），这是一种智力残疾疾病，伴有严重的生长发育迟缓、心脏异常、易患肿瘤和神经异常。超过80%的患者携带与典型、相对一致表型相关的HRAS突变c.34G>A（p.Gly12Ser）。罕见突变发生在表型减弱且面部特征不典型的个体中。大多数致病性HRAS改变影响HRAS水解活性，导致组成性激活。关于下游通路的“功能获得”和“过度激活”被广泛用于解释分子基础，而RAS-MAPK通路的失调是各种RAS病共有的生物学机制。对RAS病的panel检测在三名具有科斯特洛综合征减弱特征的个体中发现了一种新的HRAS突变（c.179G>A；p.Gly60Asp）。其中两名个体的突变源自新发父系，第三名个体的突变来自杂合母亲的遗传。这些个体面部特征细微；三人有卷发和相对头大；两人有心房性心动过速和学习困难，一人有肺动脉瓣发育异常和左心室轻度增厚。没有人有严重的生长发育迟缓、智力残疾或癌症，这突出表明对于具有非特异性RAS病表型的个体需要考虑HRAS突变。功能研究显示HRAS（Gly60Asp）与RAF1的结合显著增加，但与其他信号效应器的结合未增加。MAPK下游信号通路没有过度激活。我们的结果表明，RAS下游信号成分激活比例的增加并不能完全解释CS的分子基础。我们得出结论，CS的表型变异性概括了分子功能障碍的可变性质。
