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General Information
Name
amyotrophic lateral sclerosis 14
FlyBase ID
FBhh0000021
Overview

This report describes amyotrophic lateral sclerosis 14 (ALS14), which is a subtype of amyotrophic lateral sclerosis; ALS14 exhibits autosomal dominant inheritance. The human gene implicated in this disease is VCP, which encodes valosin-containing protein, a multifunctional member of the AAA+ (ATPase associated with various activities) protein family, which is required for the export of endoplasmic reticulum to the cytosol. This gene is also associated with the disease inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 1, IBMPFD1 (OMIM:167320, FBhh0000075). There is one high-scoring fly ortholog, TER94, for which RNAi targeting constructs, alleles caused by insertional mutagenesis, and classical amorphic alleles have been generated.

Multiple UAS constructs of the human Hsap\VCP gene have been introduced into flies, including wild-type and genes carrying mutational lesions. Heterologous rescue (functional complementation) has been demonstrated for the larval muscle phenotype.

Variant(s) implicated in human disease tested (as transgenic human gene, VCP): the R155H variant form of the human gene has been introduced into flies. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): R152H in the fly TER94 gene (corresponds to R155H in the human VCP gene), R188Q in the fly TER94 gene (corresponds to R191Q in the human VCP gene). These variants are all associated with both ALS14 and IBMPFD1; additional variants have been characterized that are associated only with IBMPFD1 (see FBhh0000075).

Amorphic and most loss-of-function alleles of Dmel\TER94 are lethal, typically during the larval stage; disruption of sarcoplasmic lysosomal tubular network is observed in muscles of mutant larvae. Targeted knockdown via RNAi results in neuroanatomy defective and learning defective phenotypes. Physical and genetic interactions of Dmel\TER94 have been described; see below and in the TER94 gene report.

When expressed in transgenic flies, the human Hsap\ATXN3 protein has been shown to interact with the Dmel\TER94 protein; ATXN3 is implicated in Machado-Joseph disease, a form of spinocerebellar ataxia (see FBhh0000063). This interaction is dependent upon the identified VCP-binding site in the human ATXN3 protein.

[updated Dec. 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 14
OMIM report

[AMYOTROPHIC LATERAL SCLEROSIS 14 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA; ALS14](https://omim.org/entry/613954)

Human gene(s) implicated

[VALOSIN-CONTAINING PROTEIN; VCP](https://omim.org/entry/601023)

Symptoms and phenotype

Pathogenic variants in VCP, encoding valosin-containing protein, have been reported in an Italian family with autosomal dominant ALS. All affected individuals displayed upper motor neuron and lower motor neuron signs, and electomyogram studies revealed denervation and chronic reinnervation changes. Five individuals followed a rapidly progressive course [Johnson et al. 2010, pubmed:21145000]. [From GeneReviews, Amyotrophic Lateral Sclerosis Overview, pubmed:20301623, 2015.12.16]

Genetics

ALS14 is caused by heterozygous mutation in the VCP gene. [from OMIM:613954, 2015.02.12]

Cellular phenotype and pathology
Molecular information

The VCP gene encodes valosin-containing protein, a ubiquitously expressed multifunctional protein that is a member of the AAA+ (ATPase associated with various activities) protein family. It has been implicated in multiple cellular functions ranging from organelle biogenesis to ubiquitin-dependent protein degradation. (Kanekura et al., 2006, pubmed:16891305)[from OMIM:601023, 2015.02.12]

External links
Disease synonyms
ALS14
amyotrophic lateral sclerosis 14, with or without frontotemporal dementia; ALS14
motor neurone disease
amyotrophic lateral sclerosis type 14
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 (See DIOPT, link below).

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    NA (TER94) encodes a protein that operates as a hexamere, functioning as a ubiquitin-dependent molecular chaperone. The hexamere associates with different co-factors to process nuclear and cytoplasmic substrates marked by ubiquitin. [Date last reviewed: 2019-09-26]
    Gene Groups / Pathways
    Comments on ortholog(s)

    Ortholog of human VCP (1 Drosophila to 1 human).

    Dmel\TER94 shares 83% identity and 92% similarity with human VCP.

    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 (96 groups)
    protein-protein
    Interacting group
    Assay
    References
    anti tag coimmunoprecipitation, western blot
    anti tag coimmunoprecipitation, anti tag western blot
    anti bait coimmunoprecipitation, western blot
    experimental knowledge based
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    experimental knowledge based
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    anti tag coimmunoprecipitation, western blot, peptide massfingerprinting
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    anti tag coimmunoprecipitation, Identification by mass spectrometry, anti tag western blot, western blot
    experimental knowledge based
    experimental knowledge based
    anti tag coimmunoprecipitation, anti tag western blot
    anti bait coimmunoprecipitation, western blot, pull down
    experimental knowledge based
    anti tag coimmunoprecipitation, western blot
    experimental knowledge based
    experimental knowledge based
    experimental knowledge based
    experimental knowledge based
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    anti tag coimmunoprecipitation, peptide massfingerprinting
    experimental knowledge based
    experimental knowledge based, inferred by curator
    experimental knowledge based
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    pull down, western blot, anti tag coimmunoprecipitation
    experimental knowledge based
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    experimental knowledge based
    anti tag coimmunoprecipitation, anti tag western blot
    experimental knowledge based
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, anti tag western blot
    experimental knowledge based
    experimental knowledge based
    experimental knowledge based
    experimental knowledge based
    anti tag coimmunoprecipitation, anti tag western blot
    experimental knowledge based
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    anti bait coimmunoprecipitation, western blot
    experimental knowledge based
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    anti tag coimmunoprecipitation, anti tag western blot, western blot, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    experimental knowledge based
    experimental knowledge based
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, anti tag western blot
    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
    anti bait coimmunoprecipitation, western blot
    anti bait coimmunoprecipitation, cross-linking study, Identification by mass spectrometry
    experimental knowledge based
    anti tag coimmunoprecipitation, anti tag western blot
    Alleles Reported to Model Human Disease (Disease Ontology) (21 alleles)
    Models Based on Experimental Evidence ( 6 )
    Modifiers Based on Experimental Evidence ( 13 )
    Allele
    Disease
    Interaction
    References
    Models Based on Experimental Evidence ( 0 )
    Allele
    Disease
    Evidence
    References
    Modifiers Based on Experimental Evidence ( 6 )
    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
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    Transgene
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    RNAi constructs available
    Allele
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    Selected Drosophila classical alleles
    Allele
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    Mutagen
    Publicly Available Stocks
    References (14)