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General Information
Name
Noonan syndrome 3
FlyBase ID
FBhh0001246
Disease Ontology Term
Parent Disease
Overview

This report describes Noonan syndrome 3 (NS3), a sub-type of Noonan syndrome; NS3 exhibits autosomal dominant inheritance. The human gene implicated in NS3 is KRAS, one of three RAS genes in human. The RAS proteins are GDP/GTP-binding proteins that act as intracellular signal transducers and are crucial players in many signaling networks affecting cell cycle progression, growth, migration, cytoskeletal changes, apoptosis, and senescence. Mutations in one of the RAS genes are among the most common events in human cancers; individuals with Noonan syndrome are at a greater risk of developing childhood cancers.

In Drosophila, Ras85D is the highest-scoring ortholog of the three human RAS genes, KRAS, NRAS, and HRAS. Classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for Ras85D. There are multiple other paralogous and orthologous genes in both species.

The human KRAS gene has not been introduced into flies.

Animals homozygous for loss-of-function alleles of Dmel\Ras85D die during the larval stage. A variant analogous to one implicated in NS3 has been created in the Drosophila gene. This mutation has been used to investigate the role of Ras85D in the formation of long-term memory, which may address aspects of the cognitive defects observed in NS3.

Variant(s) implicated in human disease tested (as analogous mutation in fly gene): V152G in the fly Ras85D gene (corresponds to V152G in the human KRAS gene). Although this C-terminal KRAS mutation is isoform-specific (affects isoform represented by UniProt P01116-2), both human protein isoforms have a valine at this position and align to the same region of the single Dmel\Ras85D isoform.

Hypertrophic cardiomyopathy is found in 20%-30% of individuals with Noonan syndrome. This aspect of NS has also been modeled in flies using the Ras85D gene; see ‘cardiomyopathy, hypertrophic (postulated), RAS-related’ (FBhh0000757).

[updated Aug. 2020 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 3
OMIM report

[NOONAN SYNDROME 3; NS3](https://omim.org/entry/609942)

Human gene(s) implicated

[KRAS PROTOONCOGENE, GTPase; KRAS](https://omim.org/entry/190070)

Symptoms and phenotype
Genetics

This form of Noonan syndrome (NS3) is caused by heterozygous mutation in the KRAS gene. [from OMIM:609942; 2020.08.21]

Cellular phenotype and pathology
Molecular information
External links
Disease synonyms
NS3
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 many: multiple paralogs and orthologs in both species.

    Other mammalian ortholog(s) used
      D. melanogaster Gene Information (1)
      Gene Snapshot
      Ras oncogene at 85D (Ras85D) encodes a protein that acts downstream of several cell signals, most notably from Receptor Tyrosine Kinases, to regulate tissue growth and development. When abnormally activated it can direct developmental defects and tissue hyperplasia, mimicking aspects of human disease including Rasopathies and cancer, respectively. [Date last reviewed: 2019-03-14]
      Cellular component (GO)
      Gene Groups / Pathways
      Comments on ortholog(s)

      High-scoring ortholog of human genes KRAS, HRAS, and NRAS (many to many; multiple paralogs and orthologs in both species). Dmel\Ras85D shares 78-86% identity and 86-92% similarity with KRAS, HRAS, and NRAS; for these three human genes, Ras85D is the highest-scoring ortholog in Drosophila.

      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 (27 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, autoradiography, two hybrid
        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
        gtpase assay, autoradiography
        anti tag coimmunoprecipitation, peptide massfingerprinting
        pull down, western blot, two hybrid
        anti tag coimmunoprecipitation, peptide massfingerprinting
        anti tag coimmunoprecipitation, anti tag western blot, two hybrid, pull down
        pull down, 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, anti tag western blot
        Alleles Reported to Model Human Disease (Disease Ontology) (13 alleles)
        Models Based on Experimental Evidence ( 4 )
        Allele
        Disease
        Evidence
        References
        Modifiers Based on Experimental Evidence ( 11 )
        Allele
        Disease
        Interaction
        References
        model of  cancer
        is ameliorated by Sec6GD11616
        is ameliorated by Sec8KK101531
        is ameliorated by Sec15GD12109
        is ameliorated by Sec151
        is ameliorated by Src64BGD12263
        is exacerbated by Nek2UAS.GFP
        is ameliorated by JraNIG.2275R
        is ameliorated by bskDN.UAS
        is ameliorated by bskHMS00777
        is exacerbated by hepAct.UAS
        is exacerbated by imdUAS.cGa
        is ameliorated by TimpUAS.cPa
        ameliorates  cancer
        model of  prostate cancer
        model of  kidney cancer
        is ameliorated by Pka-C1B3
        is ameliorated by TorΔP
        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
        loss of function allele
        loss of function allele
        P-element activity
        amorphic allele - genetic evidence
        References (5)