Noonan, Costello and cardio-facio-cutaneous syndromes: Dysregulation of the Ras-MAPK pathway

Department of Anatomy, University of California San Francisco, CA 94115, USA.
Expert Reviews in Molecular Medicine (Impact Factor: 5.15). 02/2008; 10:e37. DOI: 10.1017/S1462399408000902
Source: PubMed


A class of developmental disorders caused by dysregulation of the Ras-induced mitogen-activated protein kinase (MAPK) cascade (the Ras-MAPK pathway) has emerged. Three of these disorders - Noonan, Costello and cardio-facio-cutaneous syndromes - have overlapping phenotypic features characterised by distinctive facial dysmorphia, cardiac defects, musculoskeletal and cutaneous abnormalities, and neurocognitive delay. The germline mutations associated with these disorders are in genes that encode proteins of the Ras-MAPK pathway. In vitro studies have determined that the overwhelming majority of these mutations result in increased signal transduction down the pathway, but usually to a lesser degree than somatic mutations in the same genes that are associated with cancer. The Ras-MAPK pathway is essential in the regulation of the cell cycle, differentiation, growth and senescence, so it is not surprising that germline mutations that affect its function have profound effects on development. Here we review the clinical consequences of the known molecular lesions associated with Noonan syndrome, Costello syndrome and cardio-facio-cutaneous syndrome, and explore possible therapeutic modalities for treatment.

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    • "CFC syndrome phenotypically overlaps with Noonan syndrome (NS) and Costello syndrome (CS) since genes that are mutated in all three of these syndromes encode proteins that function in the Ras/mitogen-activated protein kinase (MAPK) signalling pathway and therefore they are all called RASopathies (4). There are four genes associated with CFC; KRAS, BRAF, MEK1 and MEK2 (5,6); approximately 75% of patients with a molecular diagnosis have BRAF mutations (4). "
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    ABSTRACT: Cardio-facio-cutaneous (CFC) syndrome is a rare disorder characterized by craniofacial dysmorphia, ectodermal abnormalities, cardiac malformations, as well as growth and developmental delay. Although some endocrine abnormalities have been reported in this syndrome, very little is known about CFC syndrome-related endocrine disorders. A 7.5-year-old boy was admitted to our endocrinology clinic with the complaint of short stature. He had a height of 103 cm [-4 standard deviation (SD)], a weight of 16 kg (<3th percentile, -1.7 SD), a facial appearance typical for the CFC syndrome, optic nerve hypoplasia and pulmonary stenosis. Genetic investigation revealed a heterozygous mutation in exon 3 of the MEK1 gene, c.389A>G (p. Y130C). During his long-term follow-up, the patient developed a variety of endocrine disorders including precocious puberty, growth hormone deficiency and hyperprolactinemia.
    Journal of Clinical Research in Pediatric Endocrinology 03/2014; 6(1):55-8. DOI:10.4274/Jcrpe.1151
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    • "To our knowledge, no study has shown that overactivation of FGFR1 is linked to HCM. However, mutations that lead to increased Ras activity, a known mediator of the FGF signaling cascade, are associated with the development of HCM (as well as a host of other cardiac and syndromic defects) [39]. To determine the mechanisms that lead to hypercontractility and the development of HCM in this model, we examined pathways known to be activated by FGFRs (ERK1/2, p38, JNK, Akt, PLCγ1, Stat3, Stat5), but changes tended to be transient and inconsistent, and thus inconclusive. "
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    ABSTRACT: Fibroblast growth factors (FGFs) and their receptors are highly conserved signaling molecules that have been implicated in postnatal cardiac remodeling. However, it is not known whether cardiomyocyte-expressed FGF receptors are necessary or sufficient for ventricular remodeling in the adult heart. To determine whether cardiomyocytes were competent to respond to an activated FGF receptor, and to determine if this signal would result in the development of hypertrophy, we engineered a doxycycline (DOX)-inducible, cardiomyocyte-specific, constitutively active FGF receptor mouse model (αMHC-rtTA, TRE-caFgfr1-myc). Echocardiographic and hemodynamic analysis indicated that acute expression of caFGFR1 rapidly and directly increased cardiac contractility, while chronic expression resulted in significant hypertrophy with preservation of systolic function. Subsequent histologic analysis showed increased cardiomyocyte cross-sectional area and regions of myocyte disarray and fibrosis, classic features of hypertrophic cardiomyopathy (HCM). Analysis of downstream pathways revealed a lack of clear activation of classical FGF-mediated signaling pathways, but did demonstrate a reduction in Serca2 expression and troponin I phosphorylation. Isolated ventricular myocytes showed enhanced contractility and reduced relaxation, an effect that was partially reversed by inhibition of actin-myosin interactions. We conclude that adult cardiomyocytes are competent to transduce FGF signaling and that FGF signaling is sufficient to promote increased cardiomyocyte contractility in vitro and in vivo through enhanced intrinsic actin-myosin interactions. Long-term, FGFR overexpression results in HCM with a dynamic outflow tract obstruction, and may serve as a unique model of HCM.
    PLoS ONE 12/2013; 8(12):e82979. DOI:10.1371/journal.pone.0082979 · 3.23 Impact Factor
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    • "NO may also play a role in epileptiform hyperactivity, as anticonvulsants diminish NO levels (Vega Rasgado et al., 2011). It is therefore relevant that up to 60% of NF1 and Rasopathy patients present with hyperactivity (Acosta et al., 2012; Tidyman and Rauen, 2008). Six weeks of NAC treatment increased locomotor activity in WT mice. "
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    ABSTRACT: 2013 Mayes, D.A., Rizvi, T.A., Titus-Mitchell, H.E., Oberst, R., Ciraolo, G., Vorhees, C.V., Cancelas, J.A., Robinson, P.R., Stemmer-Rachamimov, A.O., Ratner, N. (2013) Nf1 loss or HRas-G12V in Oligodendrocytes induce NOS-driven Defect in Myelin and Vasculature. International Society of Neurochemistry, Cancun, Mexico. Presented by Mayes.
    International Society of Neurochemistry; 04/2013
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