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General Information
Name
neurofibromatosis, type 1
FlyBase ID
FBhh0000197
Disease Ontology Term
Parent Disease
Overview

This report describes general characteristics of neurofibromatosis, type 1 (NF1); NF1 is inherited as an autosomal dominant. The human gene implicated in this disease is NF1, which encodes a tumor suppressor protein that appears to function as a regulator of the Ras signal transduction pathway. The NF1 gene is also associated with neurofibromatosis-Noonan syndrome (OMIM:601321), juvenile myelomonocytic leukemia (OMIM:607785), neurofibromatosis, familial spinal (OMIM:162210), and Watson syndrome (OMIM:193520). There is a single fly ortholog, Nf1, for which classical amorphic and loss of function alleles, RNAi-targeting constructs and alleles caused by insertional mutagenesis have been generated.

Multiple UAS constructs of the human gene Hsap\NF1 have been introduced into flies, including wild-type NF1 and NF1 genes carrying mutational lesions. Experiments using human Hsap\NF1 mutations and partial deletions, expressed in flies amorphic for Dmel\Nf1, show that separate domains of NF1 control the different adenylyl cyclase pathways observed in flies.

Variant(s) implicated in human disease tested (as transgenic human gene, NF1): the L847P, R1276P, R1391S (R1412S) and K1423E (K1444E) variant forms of the human gene have been introduced into flies. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): R1320P in the fly Nf1 gene (corresponds to R1276P in the human NF1 gene).

Animals that are homozygous for amorphic allele(s) of Dmel\Nf1 are smaller than wild-type, have a shorter lifespan, exhibit reduced tolerance for various stress conditions, and lack circadian locomotor rhythmicity. An increased frequency of attention deficit hyperactivity disorder and sleep disorders have been observed in individuals with neurofibromatosis 1; these aspects of the disease have also been investigated using Nf1 loss-of-function genotypes in flies. Physical and genetic interactions of the Dmel\Nf1 protein product have been described; see below and in the FlyBase gene report for Nf1.

[updated Oct. 2017 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: neurofibromatosis, type 1
OMIM report

[NEUROFIBROMATOSIS, TYPE I; NF1](https://omim.org/entry/162200)

Human gene(s) implicated

[NEUROFIBROMIN 1; NF1](https://omim.org/entry/613113)

Symptoms and phenotype

Neurofibromatosis type I is characterized by cafe-au-lait spots, Lisch nodules in the eye, and fibromatous tumors of the skin. Individuals with the disorder have increased susceptibility to the development of benign and malignant tumors. [from OMIM:162200, 2016.3.17]

Neurofibromatosis type 1 (NF1) is characterized by the development of multiple benign neurofibromas and areas of hypo- or hyperpigmentation of the skin. Areas of abnormal pigmentation typically include cafe-au-lait spots (pale tan or light brown discolorations) on the skin of the trunk and other regions as well as freckling, particularly under the arms and in the groin area. Such abnormalities of skin pigmentation are often evident by one year of age and tend to increase in size and number over time. At birth or early childhood, affected individuals may have relatively large benign plexiform neurofibromas. Individuals with NF1 may also develop Lisch nodules (benign tumor-like nodules of the colored regions of the eyes) or tumors of the optic nerves (second cranial nerves). More rarely, affected individuals may develop certain malignant tumors. NF1 may also be characterized by macrocephaly and relatively short stature. Additional abnormalities may also be present, such as seizures; learning disabilities; speech difficulties; hyperactivity; and skeletal malformations, including scoliosis, bowing of the lower legs, and improper development of certain bones. In individuals with NF1, associated symptoms and findings may vary greatly in range and severity from case to case. Most people with NF1 have normal intelligence but learning disabilities appear in about 50% of children with NF1. [from NORD, NeurofibromatosisType 1 (NF1), 2016.3.17]

An increased frequency of attention deficit hyperactivity disorder (Miguel, et al., 2015, pubmed:25848279) and sleep disorders (Perez et al., 2015, pubmed:24975344) have been observed in individuals with neurofibromatosis 1.

Genetics

Neurofibromatosis type I is an autosomal dominant disorder. The worldwide incidence of NF1 is 1 in 2,500 to 1 in 3,000 individuals. [from OMIM:162200, 2016.3.17]

Cellular phenotype and pathology
Molecular information

NF1 product stimulates the GTPase activity of Ras and may regulate Ras. [from UniProt, P21359 (NF1_human), 2016.4.26] NF1 appears to function as a negative regulator of the ras signal transduction pathway. [from Entrez Gene, NF1 (human), 2016.4.26]

External links
Disease synonyms
NF1
neurofibromatosis, peripheral type
Von Recklinghausen disease
Von Recklinghausen syndrome
Von Recklinghausen's disease
Von Recklinghausen's neurofibromatosis
Recklinghausen Disease, Nerve
Recklinghausen's phakomatosis
peripheral neurofibromatosis
neurofibroma, multiple
neurofibromatosis-pheochromocytoma-duodenal carcinoid syndrome
Search term: RASopathy
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

One to one: 1 human to 1 Drosophila.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    Neurofibromin 1 (Nf1) encodes a protein that functions as a GTPase activating protein for the products of Ras85D and Ras64B in the larval and adult nervous system. Loss of Nf1 results in excess Ras-Raf-ERK signaling and to a non-cell-autonomous cAMP/PKA signaling defect. The product of Nf1 contributes to postembryonic growth, learning/memory, and circadian rhythm. [Date last reviewed: 2019-03-14]
    Molecular function (GO)
    Cellular component (GO)
      Gene Groups / Pathways
      Comments on ortholog(s)

      Ortholog of human (1 Drosophila to 1 human). Dmel\Nf1 shares 54% identity and 68% similarity with human NF1.

      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      Synthetic Gene(s) Used (0)
      Summary of Physical Interactions (4 groups)
      protein-protein
      Interacting group
      Assay
      References
      anti tag coimmunoprecipitation, anti tag western blot, pull down, western blot, anti bait coimmunoprecipitation
      gtpase assay, autoradiography
      gtpase assay, autoradiography
      RNA-protein
      Interacting group
      Assay
      References
      anti bait coimmunoprecipitation, partial DNA sequence identification by hybridization
      Alleles Reported to Model Human Disease (Disease Ontology) (7 alleles)
      Models Based on Experimental Evidence ( 7 )
      Modifiers Based on Experimental Evidence ( 3 )
      Allele
      Disease
      Interaction
      References
      is ameliorated by Raf12
      is ameliorated by rl1
      is ameliorated by jebweli
      is ameliorated by car1
      is ameliorated by elav1
      is ameliorated by cnkXE-385
      is ameliorated by amxf06362
      is ameliorated by dncKK108541
      is ameliorated by carΔ146
      is ameliorated by jebKK111857
      is exacerbated by Cul3gft2
      is ameliorated by Dap160Δ1
      is ameliorated by Dap160Δ2
      is exacerbated by Pka-C1B3
      is ameliorated by cnkE-2083
      is NOT ameliorated by RetK805A.UAS
      is ameliorated by dncML
      is ameliorated by Alk8
      is ameliorated by dor8
      is ameliorated by Dsor1LH110
      is ameliorated by amxGD1168
      is ameliorated by elavG0031
      is exacerbated by Pka-C106353
      is ameliorated by dnc1
      is ameliorated by dncM14
      is ameliorated by cnkKK109209
      is ameliorated by AlkKK102942
      is ameliorated by Dsor1GD9123
      is ameliorated by Alk1
      is ameliorated by AlkGD42
      is exacerbated by rut1
      is exacerbated by rut2080
      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
      Delta2-3 transposase
      loss of function allele
      Delta2-3 transposase
      ethyl methanesulfonate
      ethyl methanesulfonate
      References (32)