Clinical manifestations of mutations in RAS and related intracellular signal transduction factors
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.
- SourceAvailable from: Lars Björn Riecken
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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. "
ABSTRACT: Gain-of-function alterations in several components and modulators of the Ras-MAPK pathway lead to dysregulation of the pathway and cause a broad spectrum of autosomal dominant developmental disorders, collectively known as RASopathies. These findings demonstrate the importance of tight multilevel Ras regulation to safeguard signalling output and prevent aberrant activity. We have recently identified ezrin as a novel regulatory element required for Ras activation. Homozygosity mapping and exome sequencing have now revealed the first presumably disease-causing variant in the coding gene EZR in two siblings with a profound intellectual disability. Localization and membrane targeting of the altered ezrin protein appeared normal but molecular modelling suggested protein interaction surfaces to be disturbed. Functional analysis revealed that the altered ezrin protein is no longer able to bind Ras and facilitate its activation. Furthermore, expression of the altered ezrin protein in different cell lines resulted in abnormal cellular processes, including reduced proliferation and neuritogenesis, thus revealing a possible mechanism for its phenotype in humans. To our knowledge this is the first report of an autosomal recessively inherited loss-of-function mutation causing reduced Ras activity and thus extends and complements the pathogenicity spectrum of known Ras-MAPK pathway disturbances.This article is protected by copyright. All rights reservedHuman Mutation 12/2014; 36(2). DOI:10.1002/humu.22737 · 5.05 Impact Factor
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- "Aberrant activation of Erk is associated with a number of developmental defects in vertebrate organisms (Bromberg-White et al., 2012; Sala et al., 2012; Zenker, 2011). Previous studies (F) Quantification of pak1 knockdown phenotype at 24 hpf. "
ABSTRACT: Proper neural crest development and migration is critical during embryonic development, but the molecular mechanisms regulating this process remain incompletely understood. Here, we show that the protein kinase Erk, which plays a central role in a number of key developmental processes in vertebrates, is regulated in the developing neural crest by p21-activated protein kinase 1 (Pak1). Furthermore, we show that activated Erk signals by phosphorylating the transcription factor Gata6 on a conserved serine residue to promote neural crest migration and proper formation of craniofacial structures, pigment cells, and the outflow tract of the heart. Our data suggest an essential role for Pak1 as an Erk activator, and Gata6 as an Erk target, during neural crest development.Developmental Cell 05/2014; 29(3):350-9. DOI:10.1016/j.devcel.2014.04.003 · 10.37 Impact Factor
Molecular syndromology 01/2014;
- "CFC syndrome (OMIM 115150) shares many features with NS, but it is usually associated with more severe learning disabilities and ectodermal (skin and hair) abnormalities [Aoki et al., 2008; Tartaglia et al., 2011; Roberts et al., 2013]. It is also predominantly associated with mutations occurring in the BRAF gene, followed by MEK1 , MEK2 and KRAS [Niihori et al., 2006; Sarkozy et al., 2009; Tartaglia and Gelb, 2010; Zenker, 2011; Roberts et al., 2013]. LS (OMIM 151100) is an acronymic name for an NSlike condition with multiple lentigines as the most distinguishing feature. "