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General Information
Name
amyotrophic lateral sclerosis 15 with or without frontotemporal dementia
FlyBase ID
FBhh0000823
Overview

This report describes amyotrophic lateral sclerosis 15 (ALS15), which is a subtype of amyotrophic lateral sclerosis; ALS15 exhibits sex-linked dominant inheritance. An alternative title for ALS15 is 'amyotrophic lateral sclerosis 15, with or without frontotemporal dementia'. The human gene implicated in this disease is UBQLN2, which encodes one of a family of ubiquitin-like proteins that play a role in the regulation of different protein degradation pathways and are thought to functionally link the ubiquitination machinery to the proteasome. There is a single orthologous gene in Drosophila, Dmel\Ubqn, for which RNAi-targeting constructs and alleles caused by insertional mutagenesis have been generated. Dmel\Ubqn is also orthologous to other ubiquilins in human, including UBQLN1 and UBQLN4.

Multiple UAS constructs of the human Hsap\UBQLN2 gene have been introduced into flies, including wild-type and variants associated with ALS15. Variant(s) implicated in human disease tested (as transgenic human gene, UBQLN2): the P497H and P525S variant forms of the human gene have been introduced into flies. An Hsap\UBQLN2 transgene carrying 4 variants (P497H, P506T, P509S, and P525S) has also been characterized in flies. Pan-neuronal expression of either wild-type or disease-associated variants results climbing defects; the phenotype is more severe for the disease-associated variants. High levels of pan-neuronal expression results in lethality.

Ubiquitous reduction in Dmel\Ubqn expression effected by RNAi results in lethality. Neuronal reduction effected by RNAi results in locomotor and neuroanatomy defects; accumulation of polyubiquitinated proteins is observed. Physical and genetic interactions of Dmel\Ubqn have been described; see below and in the Ubqn gene report.

[updated Jun. 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 15 with or without frontotemporal dementia
OMIM report

[AMYOTROPHIC LATERAL SCLEROSIS 15 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA; ALS15](https://omim.org/entry/300857)

Human gene(s) implicated

[UBIQUILIN 2; UBQLN2](https://omim.org/entry/300264)

Symptoms and phenotype
Genetics

Amyotrophic lateral sclerosis-15 with or without frontotemporal dementia (ALS15) is caused by mutation in the UBQLN2 gene; it exhibits X-linked dominant inheritance. [from OMIM:300857; 2018.06.28]

Cellular phenotype and pathology
Molecular information

UBQLN2 encodes an ubiquitin-like protein that plays a role in the regulation of different protein degradation mechanisms and pathways including ubiquitin-proteasome system (UPS), autophagy and the endoplasmic reticulum-associated protein degradation (ERAD) pathway. Ubiquilins physically associate with both proteasomes and ubiquitin ligases, thus, are thought to functionally link the ubiquitination machinery to the proteasome. [Gene Cards, UBQLN2; 2018.06.29]

The UBQLN2 gene encodes ubiquilin-2, a member of the ubiquilin family of proteins that regulate the degradation of ubiquitinated proteins by the proteasome. [from OMIM:300264; 2018.06.28]

External links
Disease synonyms
ALS15
amyotrophic lateral sclerosis 15
amyotrophic lateral sclerosis 15, with or without frontotemporal dementia
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
Symbol / Name
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to many: 5 human genes to 2 Drosophila genes. Dmel\Ubqn is much more closely related to UBQLN2 than is CG31528.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    Ubiquilin (Ubqn) encodes a protein containing an N-terminal ubiquitin-like domain and a C-terminal ubiquitin-associated domain. It binds and delivers ubiquitinated, misfolded or no longer functionally required proteins to the ubiquitin-proteasome system and/or autophagy. [Date last reviewed: 2018-10-04]
    Cellular component (GO)
    Gene Groups / Pathways
      Comments on ortholog(s)

      High-scoring ortholog of human UBQLN1, UBQLN2, UBQLN4; moderate-scoring ortholog of UBQLNL and UBQLN3 (2 Drosophila to 5 human). Dmel\Ubqn shares 46-50% identity and 63-67% similarity with UBQLN1, UBQLN2, UBQLN4; it shares 26-32% identity and 44-46% similarity with UBQLNL and UBQLN3.

      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      Other Genes Used: Viral, Bacterial, Synthetic (0)
        Summary of Physical Interactions (25 groups)
        protein-protein
        Interacting group
        Assay
        References
        experimental knowledge based
        experimental knowledge based
        enzymatic study, western blot
        experimental knowledge based
        enzymatic study, western blot
        experimental knowledge based
        experimental knowledge based
        enzymatic study, western blot
        experimental knowledge based
        cosedimentation, western blot, anti bait coimmunoprecipitation
        anti bait coimmunoprecipitation, western blot, cosedimentation
        experimental knowledge based
        affinity chromatography technology, molecular sieving, western blot
        pull down, anti tag western blot
        experimental knowledge based
        anti bait coimmunoprecipitation, western blot, cosedimentation, experimental knowledge based
        affinity chromatography technology, molecular sieving, western blot
        affinity chromatography technology, molecular sieving, western blot
        affinity chromatography technology, molecular sieving, western blot, pull down, cosedimentation, anti tag western blot
        affinity chromatography technology, molecular sieving, western blot
        experimental knowledge based
        anti bait coimmunoprecipitation, western blot
        anti tag coimmunoprecipitation, western blot
        experimental knowledge based
        anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation, experimental knowledge based
        Alleles Reported to Model Human Disease (Disease Ontology) (7 alleles)
        Models Based on Experimental Evidence ( 3 )
        Modifiers Based on Experimental Evidence ( 4 )
        Models Based on Experimental Evidence ( 2 )
        Modifiers Based on Experimental Evidence ( 0 )
        Allele
        Disease
        Interaction
        References
        Alleles Representing Disease-Implicated Variants
        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
        ethyl methanesulfonate
        References (10)