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General Information
Name
amyotrophic lateral sclerosis 8
FlyBase ID
FBhh0000020
Overview

This report describes amyotrophic lateral sclerosis 8 (ALS8), which is a subtype of amyotrophic lateral sclerosis; ALS8 exhibits autosomal dominant inheritance. The human gene implicated in this disease is VAPB, which is a member of the vesicle-associated membrane protein (VAMP)-associated protein (VAP) family. This gene is also associated with the disease spinal muscular atrophy, late-onset, Finkel type (OMIM:182980, FBhh0000254). There is a single fly ortholog, Vap33, for which classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.

Multiple UAS constructs of the human Hsap\VAPB gene have been introduced into flies, including wild-type VAPB and genes carrying mutational lesions implicated in ALS8 and SMAFK; phenotypes similar to aspects of the human disease are observed. Heterologous rescue (functional complementation) has been demonstrated for one or more Dmel\Vap33 loss-of-function phenotypes.

Variant(s) implicated in human disease tested (as transgenic human gene, VAPB): the P56S variant form of the human gene has been introduced into flies. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): T48I in the fly Vap33 gene (corresponds to T46I in the human VAPB gene); P58S in the fly Vap33 gene (corresponds to V234I in the human VAPB gene); V260I in the fly Vap33 gene (corresponds to V234I in the human VAPB gene). The P56S variant is also associated with spinal muscular atrophy, late-onset, Finkel type (see FBhh0000254).

For loss-of-function mutations in the Dmel\Vap33 gene, observed phenotypes include aspects similar to the human disease, including progressive locomotor defects, neurophysiology and neuroanatomy defects, and shortened lifespan. Physical and genetic interactions of Dmel\Vap33 have been described; see below and in the Vap33 gene report.

[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 8
OMIM report
[AMYOTROPHIC LATERAL SCLEROSIS 8; ALS8](https://omim.org/entry/608627)
Human gene(s) implicated
[VESICLE-ASSOCIATED MEMBRANE PROTEIN-ASSOCIATED PROTEIN B; VAPB](https://omim.org/entry/605704)
Symptoms and phenotype
ALS8 is an autosomal dominant slowly progressive disorder characterized by fasciculations, cramps, and postural tremor (Nishimura, et al., 2004, pubmed:15060112; Nishimura, et al., 2004, pubmed:15372378). [From OMIM:608627, 2015.12.16]
Genetics
ALS8 is caused by heterozygous mutation in the VAPB gene. [from OMIM:608627, 2015.02.12]
Cellular phenotype and pathology
In vitro functional expression studies in COS-7 and neuronal cells showed that the VABP T46I mutation formed intracellular protein aggregates and ubiquitin aggregates, ultimately resulting in cell death. (Chen, et al., 2010, pubmed:20940299). [from OMIM:605704 and 608627, 2015.02.12]
Molecular information
The VAPB gene encodes a protein that is a member of the vesicle-associated membrane protein (VAMP)-associated protein (VAP) family. VAPB plays a role in the unfolded protein response (UPR), a process that suppresses the accumulation of unfolded proteins in the endoplasmic reticulum (Kanekura, et al., 2006, pubmed:16891305). [from OMIM:605704, 2015.02.12]
External links
Disease synonyms
ALS8
amyotrophic lateral sclerosis 8; ALS8
Amyotrophic lateral sclerosis 8
amyotrophic lateral sclerosis 8
ALS type 8
motor neurone disease
amyotrophic lateral sclerosis type 8
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)
Many to one: 2 human to 1 Drosophila (See DIOPT, link below).
Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    VAMP-associated protein 33kDa (Vap33) encodes a protein that plays a conserved role in synaptic homeostasis. It controls a number of processes which depend on phosphoinositide levels, such as synaptic growth and axonal transport. It binds to the product of Sac1 to maintain normal levels of phosphoinositides and to the product of Dscam1 to affect its localization within axonal projections. [Date last reviewed: 2019-03-21]
    Molecular function (GO)
    Gene Groups / Pathways
      Comments on ortholog(s)
      Ortholog of human VAPB and human VAPA (1 Drosophila to 2 human; additional more distantly related gene(s) in both species).
      Dmel\Vap-33A shares 37% identity and 54% similarity with human VAPB, and 36% identity and 51% similarity with human VAPA.
      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 (24 groups)
      protein-protein
      Interacting group
      Assay
      References
      experimental knowledge based
      experimental knowledge based
      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
      anti tag coimmunoprecipitation, peptide massfingerprinting, pull down, western blot, anti bait coimmunoprecipitation
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, anti tag western blot
      proximity ligation assay, fluorescence microscopy, anti tag coimmunoprecipitation, anti tag western blot, pull down, Identification by mass spectrometry
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      anti tag coimmunoprecipitation, anti tag western blot, two hybrid
      proximity ligation assay, fluorescence microscopy
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, anti tag western blot
      Alleles Reported to Model Human Disease (Disease Ontology) (9 alleles)
      Models Based on Experimental Evidence ( 8 )
      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
      amorphic allele - molecular evidence
      P-element activity
      References (27)