Article

Clinical manifestations of mutations in RAS and related intracellular signal transduction factors

Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.
Current opinion in pediatrics (Impact Factor: 2.74). 08/2011; 23(4):443-51. DOI: 10.1097/MOP.0b013e32834881dd
Source: PubMed

ABSTRACT Recent advances in molecular genetic research have led to the definition of the new group of genetic syndromes, the RAS-mitogen-activated protein kinase (MAPK) pathway disorders or 'RASopathies'. They comprise Noonan syndrome and related disorders (cardio-facio-cutaneous and Costello syndromes), as well as neurofibromatosis type 1. This review summarizes the recent literature with a special focus on genotype-phenotype correlations.
Although the picture is still incomplete, and additional genes are likely to exist, the underlying genetic alteration can now be found in a large majority of patients with a RASopathy phenotype. The most recently discovered novel genes for Noonan syndrome or Noonan syndrome-like disorders, NRAS, SHOC2, and CBL, account for small fractions of the patient population. The increasing knowledge about the spectrum of gene mutations and associated clinical manifestations has led to a refinement of genotype-phenotype correlations. Recent studies have added new insights into tumor predisposition and prenatal manifestations. Model systems are being developed to investigate innovative treatment approaches.
Constitutional overactivation at various levels of the RAS-MAPK pathway causes overlapping syndromes, comprising characteristic facial features, cardiac defects, cutaneous abnormalities, growth deficit, neurocognitive delay, and predisposition to malignancies. Each syndrome also exhibits unique features that probably reflect genotype-related specific biological effects.

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    • "RASopathies (Schubbert et al. 2007; Zenker 2011; Rauen 2013; Roberts et al. 2013), are characterized by an over-activation of the pathway and are uniformly inherited in an autosomal dominant manner. In contrast, our mapping, sequencing and functional data strongly indicate that the identified variant in EZR presents the first autosomal recessively inherited loss-of-function variant in the Ras-MAPK pathway and thus may represent a counterpart to the classic RASopathies. "
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