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General Information
Name
Noonan syndrome 5
FlyBase ID
FBhh0000131
Disease Ontology Term
Parent Disease
Overview

This report describes Noonan syndrome 5 (NS5), which is a subtype of Noonan syndrome; NS5 exhibits autosomal dominant inheritance. The human gene implicated in this disease is RAF1, which encodes Raf-1 proto-oncogene, serine/threonine kinase, a kinase that acts within the RAS-RAF-MEK-ERK pathway. RAF1 is also associated with the diseases Noonan syndrome with multiple lentigines 2 (OMIM:611554, FBhh0000132) and dilated cardiomyopathy-1NN (OMIM:615916, FBhh0000156). See, in addition, FBhh0000558, a fly model of RAS-RAF-MEK-ERK-pathway-related cancer using RAF1. There is one high-scoring fly ortholog, Raf, for which RNAi targeting constructs, alleles caused by insertional mutagenesis, and classical amorphic alleles have been generated. Dmel\Raf is orthologous to two additional human genes, ARAF and BRAF. BRAF is also associated with a form of Noonan syndrome (see FBhh0001344).

Multiple transgenic constructs of the human Hsap\RAF1 gene have been introduced into flies, including wild-type, genes carrying disease-implicated variants, gain-of-function RAF1, and genes carrying an N-terminal deletion. Functional conservation between the human and fly genes has been demonstrated in fly several systems; for example, an activated form of the human gene has been shown to recapitulate phenotypes observed for an activated form of, or overexpression of, the fly gene. Variant(s) implicated in human disease tested (as transgenic human gene, RAF1): the S275L, D486G, and L613V variant forms of the human gene have been introduced into flies; the S275L and L613V variants are also implicated in Noonan syndrome with multiple lentigines 2 (FBhh0000132). Experiments with the human variants include assessments of pharmaceutical candidates.

Hypertrophic cardiomyopathy, which is frequently observed in NS5 patients, has been investigated in fly models using the human Hsap\RAF1 gene and the fly Raf gene; see 'cardiomyopathy, hypertrophic (postulated), RAF-related' (FBhh0000737).

Animals homozygous for amorphic mutations of Dmel\Raf exhibit lethality in the late larval stage; imaginal discs are undeveloped. Embryos lacking all Dmel\Raf activity (derived from homozygous null germline clones in the mother and not rescued by paternal contribution) die in early embryogenesis. A transgenic mutation of Dmel\Raf analogous to a disease-implicated variant in human has been studied. Variant(s) implicated in human disease introduced (as analogous mutation in fly gene): S346A in the fly Raf gene (corresponds to S259A in the human RAF1 gene); this construct was used for assessments of pharmaceutical candidates. Many physical and genetic interactions have been described for Dmel\Raf; see below and in the gene report for Raf.

[updated May 2021 by FlyBase; FBrf0222196]

Disease Summary Information
Parent Disease Summary: Noonan syndrome
Symptoms and phenotype

Noonan syndrome (NS) is an autosomal dominant disorder characterized by short stature, facial dysmorphism, and a wide spectrum of congenital heart defects. The distinctive facial features consist of a broad forehead, hypertelorism, downslanting palpebral fissures, a high-arched palate, and low-set, posteriorly rotated ears. Cardiac involvement is present in up to 90% of patients. Pulmonic stenosis and hypertrophic cardiomyopathy are the most common forms of cardiac disease, but a variety of other lesions are also observed. Additional relatively frequent features include multiple skeletal defects (chest and spine deformities), webbed neck, mental retardation, cryptorchidism, and bleeding diathesis (summary by Tartaglia et al., 2002 pubmed:11992261). [from OMIM:163950, 2015.04.14]

Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. [Gene Reviews, Noonan Syndrome, 2020.08.21]

Specific Disease Summary: Noonan syndrome 5
OMIM report

[NOONAN SYNDROME 5; NS5](https://omim.org/entry/611553)

Human gene(s) implicated

[RAF1 PROTOONCOGENE, SERINE/THREONINE KINASE ; RAF1](https://omim.org/entry/164760)

Symptoms and phenotype

Of 17 Noonan syndrome patients with a RAF1 mutation in either of two hotspots (clustering around ser259 or ser612), 16 (94%) had hypertrophic cardiomyopathy (CMH; see OMIM:192600), compared with an 18% prevalence of CMH among Noonan syndrome patients in general (Pandit et al., 2007, pubmed:17603483). Pandit et al. (2007) also scanned RAF1 exons mutated in Noonan and LEOPARD syndrome patients in 241 unrelated individuals with nonsyndromic CMH who did not have mutations in 8 myofilament genes known to cause CMH, and the authors identified a thr260-to-ile mutation in the RAF1 gene in one patient (Pandit et al., 2007, pubmed:17603483). [from OMIM:164760, 2016.01.19]

The studies reported to date emphasize a striking correlation with hypertrophic cardiomyopathy, with 95% of affected individuals with a RAF1 mutation showing this feature, in comparison with the overall prevalence in Noonan syndrome of 18%. This suggests that pathologic cardiomyocyte hypertrophy occurs because of increased Ras signaling. Multiple nevi, lentigines, and/or café au lait spots were reported in one third of people with RAF1-associated Noonan syndrome. [from GeneReviews, Noonan Syndrome, pubmed:20301303 2016.01.20]

Genetics

Noonan syndrome 5 (NS5) is caused by mutation in the RAF1 gene. LEOPARD syndrome-2 (OMIM:611554) is also caused by mutation in RAF1, indicating that the 2 disorders are allelic. [From OMIM:611553, 2016.01.15]

Cellular phenotype and pathology
Molecular information

RAF1 is a serine-threonine kinase that activates MEK1 (OMIM:176872) and MEK2 (OMIM:601263). Ectopically expressed RAF1 mutants from the two hypertrophic cardiomyopathy (CMH; see OMIM:192600) hotspots (around ser259 or ser612) linked to LEOPARD syndrome 2 and/or Noonan syndrome 5 had increased kinase activity and enhanced ERK (see 176948) activation, whereas non-CMH-associated mutants were kinase impaired. (Pandit et al., 2007, pubmed:17603483). Mutations in the CR2 domain, but not the CR3 domain, of RAF1 are associated with hypertrophic cardiomyopathy (Razzaque et al., 2007, pubmed:17603482). [From OMIM:611553 and OMIM:164760, 2016.01.19]

RAF1 is ubiquitously expressed and encodes a protein of 648 amino acids with three conserved regions (CR). CR1 contains a Ras-binding domain; CR2 is a site of regulatory phosphorylation and association with the 14-3-3 protein. CR1 and CR2 both have negative regulatory function, removal of which results in oncogenic activity. The kinase domain, CR3, also associates with 14-3-3. The protein is highly regulated with numerous serine and threonine residues that can be phosphorylated, resulting in activation or inactivation. The serine at residue 259, which is in CR2, is particularly important. In the inactive state, the N-terminus of RAF1 interacts with and inactivates the kinase domain at the C-terminus. This conformation is stabilized by 14-3-3 protein dimers that bind to phosphorylated Ser259 and Ser261. Dephosphorylation of Ser259 facilitates binding of RAF1 to RAS-GTP and propagation of the signal through the RAS-MAPK cascade via RAF1 MEK kinase activity. [from GeneReviews, Noonan Syndrome with Multiple Lentigines, pubmed:20301557 2016.01.20]

External links
Disease synonyms
Noonan syndrome 5; NS5
NS5
Search term: RASopathy
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to one: 3 human to 1 Drosophila.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    Raf oncogene (Raf) encodes a serine-threonine protein kinase that acts downstream of the product of Ras85D. It activates the MEK/ERK pathway to regulate cell proliferation, differentiation and survival downstream of receptor tyrosine kinases such as those encoded by tor, Egfr, and sev. [Date last reviewed: 2019-03-14]
    Cellular component (GO)
    Gene Groups / Pathways
    Comments on ortholog(s)

    Ortholog of human BRAF, ARAF, and RAF1 (1 Drosophila to 3 human).

    Dmel\Raf shares 43% identity and 54% similarity with human BRAF, 44% identity and 58% similarity with human ARAF, and 47% identity and 60% similarity with human RAF1.

    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    Other Genes Used: Viral, Bacterial, Synthetic (0)
      Summary of Physical Interactions (89 groups)
      protein-protein
      Interacting group
      Assay
      References
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, anti tag western blot, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      enzymatic study, autoradiography
      anti tag coimmunoprecipitation, western blot, two hybrid, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting, two hybrid
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, anti tag western blot, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, anti tag western blot, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting, anti tag western blot
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, anti tag western blot, two hybrid
      pull down, two hybrid, anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      Alleles Reported to Model Human Disease (Disease Ontology) (13 alleles)
      Models Based on Experimental Evidence ( 3 )
      Modifiers Based on Experimental Evidence ( 6 )
      Allele
      Disease
      Interaction
      References
      ameliorates  Huntington's disease
      modeled by @Huntington's??not a valid allele symbol??@, @disease??not a valid allele symbol??@
      Models Based on Experimental Evidence ( 5 )
      Modifiers Based on Experimental Evidence ( 1 )
      Allele
      Disease
      Interaction
      References
      Alleles Representing Disease-Implicated Variants
      Genetic Tools, Stocks and Reagents
      Sources of Stocks
      Contact lab of origin for a reagent not available from a public stock center.
      Bloomington Stock Center Disease Page
      Selected mammalian transgenes
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila transgenes
      Allele
      Transgene
      Publicly Available Stocks
      RNAi constructs available
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila classical alleles
      Allele
      Allele class
      Mutagen
      Publicly Available Stocks
      amorphic allele - genetic evidence
      nitrosomethyl urea
      loss of function allele
      amorphic allele - genetic evidence
      X ray
      amorphic allele - genetic evidence
      1,2-dichloroethane
      amorphic allele - genetic evidence
      spontaneous
      amorphic allele - genetic evidence
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      hycanthon methanesulfonate
      amorphic allele - genetic evidence
      ethyl methanesulfonate
      amorphic allele - genetic evidence
      ethyl methanesulfonate
      amorphic allele - genetic evidence
      X ray
      amorphic allele - genetic evidence
      ethyl methanesulfonate
      References (8)