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General Information
Name
amyotrophic lateral sclerosis 20
FlyBase ID
FBhh0000034
Overview

This report describes amyotrophic lateral sclerosis 20 (ALS20), which is a subtype of amyotrophic lateral sclerosis; ALS20 exhibits autosomal dominant inheritance. The human gene implicated in this disease is HNRNPA1, which encodes heterogeneous nuclear ribonucleoprotein A1. This gene has also been associated with the disease inclusion body myopathy with early-onset Paget disease without frontotemporal dementia 3 (IBMPFD3, OMIM:615424, FBhh0000299). There are two high-scoring fly orthologs: Hrb98DE, for which RNAi targeting constructs, alleles caused by insertional mutagenesis, and classical amorphic alleles have been generated; and Hrb87F, for which RNAi targeting constructs and classical amorphic alleles have been generated. Only Hrb98DE has been analyzed in the context of ALS20/IBMPFD3 in flies. An orthologous gene in human, HNRNPA2B1, is implicated in inclusion body myopathy with early-onset Paget disease without frontotemporal dementia 2 (IBMPFD2); see FBhh0000298.

A variant(s) implicated in IBMPFD3 (corresponds to D262V/D314V in the human HNRNPA1 gene) has been tested in flies, but no variants implicated in ALS20.

Multiple UAS constructs of the human Hsap\HNRNPA1 gene have been introduced into flies, including wild-type HNRNPA1 and a gene carrying a mutational lesion implicated in IBMPFD3. Transgenic expression of mutant constructs recapitulates some of the key phenotypes of ALS20 and IBMPFD, including degeneration of muscle fibers and the formation of cytoplasmic inclusions of mutant protein. Heterologous rescue of mutations in the Drosophila ortholog by expression of HNRNPA1 has not been tested

A UAS construct of Dmel\Hrb98DE bearing a mutation that corresponds to both the mutational lesion in HNRNPA1 that is implicated in IBMPFD3 and the mutational lesion in HNRNPA2B1 that is implicated in IBMPFD2 has been introduced into flies; it recapitulates some of the key phenotypes of ALS20 and IBMPFD, including degeneration of muscle fibers and the formation of cytoplasmic inclusions of mutant protein.

[updated Aug. 2019 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 20
OMIM report
[AMYOTROPHIC LATERAL SCLEROSIS 20; ALS20](https://omim.org/entry/615426)
Human gene(s) implicated
[HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN A1; HNRNPA1](https://omim.org/entry/164017)
Symptoms and phenotype
Genetics
ALS20 is caused by heterozygous mutation in the HNRNPA1 gene. [from OMIM:615426, 2015.04.22]
Cellular phenotype and pathology
Muscle biopsies from an affected patient showed nuclear clearance and cytoplasmic inclusions of HNRNPA1 protein in 10% of muscle fibres.
Molecular information
Disease-associated mutations are localized to the prion-like domains (PrLD) of HNRNPA1 and HNRNPA2B1. In vitro, disease-associated mutations greatly accelerate HNRNPA1 and HNRNPA2B1 fibrillization, and directly promote nucleation of wild-type HNRNPA1 and HNRNPA2B1 into fibrils.
A recent emerging theme in ALS research is the hypothesis that some ALS-associated proteins have a key role in the formation and function of cytoplasmic RNP stress granules, a cytosolic component in which non-functional translation initiation products accumulate. Stress granules form in response to a number of environmental stresses known to impede translation of mRNA into protein. Several ALS-associated proteins that have prion-like domains have been identified as accumulating in stress granules, including HNRNPA1.
Kim et al., 2013, (pubmed:23455423) reported that HNRNPA1 has a C-terminal glycine-rich domain that is essential for activity and mediates interaction with TARDBP, the protein associated with ALS10. This low-complexity domain is predicted to be intrinsically unfolded and has an amino acid composition similar to that of yeast prion domains. Approximately 250 human proteins, including several RNA-binding proteins associated with neurodegenerative disease, harbor a similar distinctive prion-like domain (PrLD) enriched in uncharged polar amino acids and glycine. PrLDs in RNA-binding proteins are essential for the assembly of ribonucleoprotein granules. Kim et al., 2013, (pubmed:23455423) showed that HNRNPA1 has an intrinsic tendency to assemble into self-seeding fibrils. Kim et al., 2013, (pubmed:23455423) screened 212 familial ALS cases for sequence variants in the HNRNPA2B1 or HNRNPA1 genes. They identified 1 dominantly inherited case in which known ALS genes had been excluded with mutation in the HNRNPA1 gene. Kim et al., 2013, (pubmed:23455423) also screened 305 sporadic ALS cases and identified a nonsynonymous HNRNPA1 variant in an individual with classic, late-onset ALS [from OMIM:164017, 2015.04.22]
External links
Disease synonyms
amyotrophic lateral sclerosis 20; ALS20
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)
Many to many: 5 human to 4 Drosophila.
Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    Heterogeneous nuclear ribonucleoprotein at 98DE (Hrb98DE) encodes a nuclear RNA-binding protein. It controls hnRNA stability, splicing, IRES-dependent translation, and translational repression. It represents one of the main targets of the poly(ADP-ribosyl)ation pathway. It also regulates tissue polarity patterning and germ-line stem cell fate. [Date last reviewed: 2019-03-07]
    Gene Groups / Pathways
    Comments on ortholog(s)
    Ortholog of human HNRNPA2B1, HNRNPA3, HNRNPA1, HNRNPA1L2, and HNRNPA0 (4 Drosophila to 5 human; additional more distantly related gene(s) in both species). Dmel\Hrb98DE shares 50% identity and 64% similarity with human HNRNPA2B1, 50% identity and 62% similarity with human HNRNPA3, 49% identity and 63% similarity with human HNRNPA1L2, 48% identity and 64% similarity with human HNRNPA1, and 44% identity and 59% similarity with human HNRNPA0.
    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 (27 groups)
    protein-protein
    Interacting group
    Assay
    References
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    experimental knowledge based
    pull down, autoradiography
    experimental knowledge based
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    proximity-dependent biotin identification, Identification by mass spectrometry
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, western blot
    experimental knowledge based
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti bait coimmunoprecipitation, molecular weight estimation by autoradiography, molecular weight estimation by staining
    anti tag coimmunoprecipitation, western blot
    far western blotting, Identification by mass spectrometry
    RNA-protein
    Interacting group
    Assay
    References
    anti bait coimmunoprecipitation, nucleotide sequence identification
    anti bait coimmunoprecipitation, reverse transcription pcr
    anti tag coimmunoprecipitation, quantitative reverse transcription pcr
    anti bait coimmunoprecipitation, reverse transcription pcr, anti tag coimmunoprecipitation, nucleic acid uv cross-linking assay, tag visualisation
    anti bait coimmunoprecipitation, reverse transcription pcr
    pull down, Identification by mass spectrometry
    anti bait coimmunoprecipitation, reverse transcription pcr
    anti bait coimmunoprecipitation, reverse transcription pcr, nucleic acid uv cross-linking assay, tag visualisation, electrophoretic mobility shift assay, quantitative reverse transcription pcr
    anti bait coimmunoprecipitation, reverse transcription pcr
    RNA-RNA
    Interacting group
    Assay
    References
    luminiscence technology
    Alleles Reported to Model Human Disease (Disease Ontology) (5 alleles)
    Models Based on Experimental Evidence ( 2 )
    Modifiers Based on Experimental Evidence ( 4 )
    Models Based on Experimental Evidence ( 1 )
    Modifiers Based on Experimental Evidence ( 0 )
    Allele
    Disease
    Interaction
    References
    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
    References (10)