Zenker MClinical manifestations of mutations in RAS and related intracellular signal transduction factors. Curr Opin Pediatr 23:443-451

Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.
Current opinion in pediatrics (Impact Factor: 2.53). 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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    • "The RASopathies have many overlapping characteristics, including craniofacial anomalies, congenital heart defects, growth impairment, cutaneous, musculoskeletal , gastrointestinal, and ocular abnormalities, as well as neurocognitive impairment and an increased risk of developing cancer [Tidyman and Rauen, 2009; Zenker, 2011]. CFC syndrome is one of the rare RASopathy syndromes. "
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    ABSTRACT: Cardiofaciocutaneous (CFC) syndrome is a rare genetic disorder belonging to the group of RASopathies. It is typically characterized by congenital heart defects, short stature, dysmorphic craniofacial features, intellectual disability, failure to thrive, and ectodermal abnormalities such as hyperkeratosis and sparse, brittle, curly hair. CFC syndrome is caused by dominant mutations in one of the four genes BRAF, MEK1, MEK2, and KRAS. Only three familial cases of CFC syndrome have been reported to date, whereas the vast majorities are sporadic cases due to de novo mutations. We report on a fourth familial case with transmission of CFC syndrome from father to son due to a novel heterozygous sequence change c.376A>G (p.N126D) in exon 3 of MEK2 gene. This observation further documents the possibility of vertical transmission of CFC syndrome, which appears to be associated with rare mutations and relatively mild intellectual disability in affected individual. The hypomorphic effect of specific mutations particularly regarding neurocognitive issues may be related to the variable fertility of affected individuals. © 2014 Wiley Periodicals, Inc. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 02/2015; 167(2). DOI:10.1002/ajmg.a.36429 · 2.16 Impact Factor
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    • "RASopathies constitute an emerging group of clinically and genetically related disorders affecting development and growth; and having RAS signaling dysregulation as shared pathogenic mechanism [Tidyman and Rauen 2009; Tartaglia et al., 2011; Zenker, 2011]. Within this family of developmental disorders, ten years ago, Mazzanti et al. [2003] recognized a distinctive phenotype characterized by short stature, macrocephaly, central nervous system (CNS) anomalies, growth hormone deficiency (GHD), and mild neurological developmental delay. "
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    ABSTRACT: Noonan-like syndrome with loose anagen hair (NS/LAH; OMIM 607721) is a developmental disorder clinically related to Noonan syndrome (NS) and characterized by facial dysmorphisms, postnatal growth retardation, cardiac anomalies (in particular dysplasia of the mitral valve and septal defects), variable neurocognitive impairment, and florid ectodermal features. A distinctive trait of NS/LAH is its association with easily pluckable, slow growing, sparse, and thin hair. This rare condition is due to the invariant c.4A > G missense (p.Ser2Gly) change in SHOC2, which encodes a regulatory protein that participate in RAS signaling. Here we report two patients with molecularly confirmed NS/LAH, with extremely different phenotypic expression, in particular concerning the severity of the cardiac phenotype and neurocognitive profile. While the first available clinical records outlined a relatively homogeneous phenotype in NS/LAH, the present data emphasize that the phenotype spectrum associated with this invariant mutation is wider than previously recognized. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 12/2014; 164(12). DOI:10.1002/ajmg.a.36697 · 2.16 Impact Factor
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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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    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 reserved
    Human Mutation 12/2014; 36(2). DOI:10.1002/humu.22737 · 5.14 Impact Factor
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