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General Information
Name
amyotrophic lateral sclerosis 18
FlyBase ID
FBhh0000023
Overview

This report describes amyotrophic lateral sclerosis 18 (ALS18), which is a subtype of amyotrophic lateral sclerosis; ALS18 exhibits autosomal dominant inheritance. The human gene implicated in this disease is profilin 1 (PFN1), which encodes an actin-monomer-binding protein. There are four profilin genes in human, PFN1, PFN2, PFN3, and PFN4; chic is the only profilin gene in flies. Classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for chic.

Multiple UAS constructs of human Hsap\PFN1 have been introduced into flies, including wild-type PFN1 and genes carrying variants implicated in ALS18. Partial heterologous rescue (functional complementation) has been observed: expression of either wild-type or mutant Hsap\PFN1 in glutamatergic neurons is sufficient to rescue the pupal lethality resulting from RNAi-effected loss of chic expression using the same GAL4 driver.

Variant(s) implicated in human disease tested (as transgenic human gene, PFN1): the C71G and M114T variant forms have been introduced into flies. Expression of human PFN1 in glutamatergic neurons results in progressive locomotion defects and shorter lifespan in adult flies; ALS-implicated PFN1 mutants display a less toxic effect. Expression in other neural tissues, such as the eye, has little or no effect.

Animals homozygous for amorphic mutations of chic die during the embryonic stage; mutant embryos exhibit developmental and neuroanatomy defects. Phenotypes in the adult brain and other late stages have been characterized using somatic clones. Muscle-specific overexpression results in elongated sarcomeres, myofibrillar disorganization, and sarcomeric disarray; these cellular phenotypes correlate with phenotypes of impaired muscle function (flight and climbing in adults). Extensive genetic and physical interactions have been described for Dmel\chic; see below and in the chic gene report.

See also the human disease model report 'cardiomyopathy, hypertrophic (postulated), profilin-related' (FBhh0000705).

[updated Apr. 2018 by FlyBase; FBrf0222196]

Disease Summary Information
Parent Disease Summary: amyotrophic lateral sclerosis
Symptoms and phenotype
Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. ALS usually begins with asymmetric involvement of the muscles in middle adult life. Approximately 10% of ALS cases are familial (Siddique and Deng, 1996, pubmed:8875253). ALS is sometimes referred to as 'Lou Gehrig disease' after the famous American baseball player who was diagnosed with the disorder. [from OMIM:105400, 2015.02.11]
Specific Disease Summary: amyotrophic lateral sclerosis 18
OMIM report
[AMYOTROPHIC LATERAL SCLEROSIS 18; ALS18](https://omim.org/entry/614808)
Human gene(s) implicated
[PROFILIN 1; PFN1](https://omim.org/entry/176610)
Symptoms and phenotype
Among 22 cases of ALS that resulted from mutations in PFN1 (ALS18), all displayed limb onset. Given that bulbar onset represents approximately 25% of ALS cases, it was proposed that their observation suggests a common clinical phenotype among patients with PFN1 mutations. The age of onset for familial ALS18 cases was 44.8 +/- 7.4 years. (Wu et al.,2012, pubmed:22801503) [from OMIM:614808, 2015.02.12]
Genetics
ALS18 is caused by heterozygous mutation in the PFN1 gene. [from OMIM:614808, 2015.02.12]
Cellular phenotype and pathology
In vitro assays showed that ALS-associated mutant PFN1 produces ubiquitinated, insoluble aggregates in transfected cells. In many cases the aggregates contained the ALS-associated protein TDP43 (TARDBP). The E117G mutation displayed a distribution more similar to that of wildtype PFN1, with most of the expressed protein in the soluble fraction. [In transfected cultured primary motor neurons] mutant PFN1 inhibited axon outgrowth. These results indicated that mutations in the PFN1 gene account for approximately 1 to 2% of familial ALS and suggested that disruption of cytoskeletal pathways contribute importantly to ALS pathogenicity (Wu et al., 2012, pubmed:22801503). [from OMIM:176610, 2015.02.12]
Molecular information
Profilin-1 is a 140-amino acid protein and major growth regulator of filamentous (F)-actin through its binding of monomeric (G)-actin. (Mockrin and Korn, 1980, pubmed:6893804). [from OMIM:176610, 2015.02.12]
External links
Disease synonyms
ALS18
amyotrophic lateral sclerosis 18; ALS18
motor neurone disease
amyotrophic lateral sclerosis type 18
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
Symbol / Name
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)
Many to one: 3 profilin genes in human, PFN4, PFN1, and PFN2 show similarity to the single Drosophila profilin, chic.
Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    chickadee (chic) encodes an actin monomer binding protein that provides the major cellular pool of readily polymerizing ATP-actin monomers. It is involved in oogenesis, spermatogenesis, cell division, bristle formation, cellular morphogenesis, axon growth, filopodia formation, dorsal closure, wound healing and stem cell maintenance. [Date last reviewed: 2019-03-07]
    Molecular function (GO)
    Gene Groups / Pathways
      Comments on ortholog(s)
      Low- to moderate-scoring ortholog of human PFN4, PFN1, and PFN2; Dmel\chic shares 28% identity and 42% similarity with PFN1 and PFN4.
      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 (45 groups)
      protein-protein
      Interacting group
      Assay
      References
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      anti bait coimmunoprecipitation, western blot, experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      anti tag coimmunoprecipitation, anti tag western blot
      experimental knowledge based
      pull down, anti tag western blot
      experimental knowledge based
      two hybrid, pull down, western blot, anti tag coimmunoprecipitation, anti tag western blot
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      anti tag coimmunoprecipitation, peptide massfingerprinting
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      RNA-protein
      Interacting group
      Assay
      References
      anti tag coimmunoprecipitation, quantitative reverse transcription pcr
      electrophoretic mobility shift assay, autoradiography, pull down, western blot, anti tag coimmunoprecipitation, quantitative reverse transcription pcr
      Alleles Reported to Model Human Disease (Disease Ontology) (9 alleles)
      Models Based on Experimental Evidence ( 2 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 2 )
      Models Based on Experimental Evidence ( 6 )
      Modifiers Based on Experimental Evidence ( 3 )
      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
      P-element activity
      amorphic allele - genetic evidence
      Delta2-3 transposase
      amorphic allele - genetic evidence
      Delta2-3 transposase
      References (8)