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General Information
Name
dentatorubral-pallidoluysian atrophy
FlyBase ID
FBhh0000214
Overview

This report describes dentatorubral-pallidoluysian atrophy (DRPLA); DRPLA is inherited as an autosomal dominant. The human gene implicated in this disease is ATN1, which encodes atrophin 1 and functions as a transcription corepressor. DRPLA is one of a number cerebellar ataxias caused by expansion of CAG repeats within the coding region of the causative gene, resulting in an expanded run of glutamine (Q) residues in the encoded protein. There is one identified fly ortholog of ATN1, Gug, for which RNAi targeting constructs, alleles caused by insertional mutagenesis, and classical amorphic alleles have been generated. Dmel\Gug is orthologous to a second human gene, RERE.

Multiple UAS constructs of the human Hsap\ATN1 gene have been introduced into flies, including wild-type ATN1, C-terminal deletion constructs, and constructs with expanded (CAG)n repeats. Expression in the adult eye results in progressive eye depigmentation and retinal collapse; conditional expression in adult stages in neural and glial cells results in reduced viability and neural defects.

Variant(s) implicated in human disease tested (as transgenic human gene, ATN1): Q484_Q502 (CAG)n EXPANSION; most experiments have used a truncated protein with the polyQ expansion.

Loss-of-function alleles of Dmel\Gug are lethal, usually during the embryonic stage; somatic clones exhibit cell polarity defects. Physical and genetic interactions have been described for Dmel\Gug; see below and in the gene report for Gug.

Extensive studies have also been done with polyglutamine-only models in flies; see the disease report for polyglutamine diseases, polyQ models (FBhh0000001).

[updated Sep. 2018 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: dentatorubral-pallidoluysian atrophy
OMIM report

[DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY; DRPLA](https://omim.org/entry/125370)

Human gene(s) implicated

[ATROPHIN 1; ATN1](https://omim.org/entry/607462)

Symptoms and phenotype

Dentatorubral-pallidoluysian atrophy (DRPLA) is a progressive disorder of ataxia, choreoathetosis, and dementia or character changes in adults and ataxia, myoclonus, epilepsy, and progressive intellectual deterioration in children. The age of onset is from one to 62 years with a mean age of onset of 30 years. The clinical presentation varies depending on the age of onset. The cardinal features in adults are ataxia, choreoathetosis, and dementia. Cardinal features in children are progressive intellectual deterioration, behavioral changes, myoclonus, and epilepsy. [from GeneReviews, DRPLA, pubmed:20301664 2016.03.10]

Genetics

Dentatorubral-pallidoluysian atrophy is caused by an expanded trinucleotide repeat in the atrophin 1 gene (ATN1). [from OMIM:125370, 2016.03.09]

Cellular phenotype and pathology

Small, round ubiquitin-immunoreactive intranuclear inclusions have been observed in both neurons and glial cells in various brain regions taken from DRPLA patients. Electron microscopy showed that such inclusions are composed of granular and filamentous structures. The findings strongly suggested that, in DRPLA, the occurrence of neuronal and glial inclusions is directly related to the causative expanded CAG repeat, that neurons are affected much more widely than previously recognized, and that glial cells are also involved in the disease process (Hayashi, et al, 1998, pubmed:9845282). Some patients with DRPLA have white matter lesions characterized neuropathologically by diffuse myelin pallor. The number of lesions correlates with increasing age, being milder in degree in juveniles and more severe in older adults. Immunoreactivity for polyglutamine in some glial nuclei was increased with larger expansions of (CAG)n repeats, indicating that oligodendrocytes are a target for the polyglutamine pathogenesis in DRPLA and may lead to white matter degeneration (Yamada, et al., 2002, pubmed:2402270). [from OMIM:125370, 2016.03.09]

Molecular information

The protein encoded by ATN1 acts a transcriptional corepressor. [from Gene Cards, ATN1; 2017.03.01]

External links
Disease synonyms
dentatorubro-pallidoluysian atrophy; DRPLA
DRPLA
myoclonic epilepsy with choreoathetosis
Naito-Oyanagi disease
NOD
Haw River syndrome
HRS
ataxia, chorea, seizures, and dementia
dentato-rubral and pallido-luysian atrophy
dentatorubro-pallidoluysian atrophy
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: 2 human to 1 Drosophila.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    Grunge (Gug) encodes a nuclear repressor protein that likely responds to Egfr signaling to control cell behavior for normal developmental patterning. [Date last reviewed: 2019-03-07]
    Cellular component (GO)
    Gene Groups / Pathways
    Comments on ortholog(s)

    Ortholog of human RERE and ATN1 (1 Drosophila to 2 human).

    Dmel\Gug shares 24% identity and 31% similarity with human RERE, and 23% identity and 31% similarity with human ATN1.

    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 (9 groups)
    RNA-RNA
    Interacting group
    Assay
    References
    quantitative reverse transcription pcr, luminiscence technology, necessary binding region
    protein-protein
    Interacting group
    Assay
    References
    anti tag coimmunoprecipitation, anti tag western blot, pull down, two hybrid
    pull down, anti tag western blot, two hybrid
    anti tag coimmunoprecipitation, anti tag western blot
    anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, anti tag western blot
    anti bait coimmunoprecipitation, anti tag western blot, pull down, autoradiography
    two hybrid, pull down, autoradiography
    bimolecular fluorescence complementation, fluorescence microscopy, pull down, autoradiography, two hybrid, anti bait coimmunoprecipitation, anti tag western blot
    anti bait coimmunoprecipitation, western blot
    Alleles Reported to Model Human Disease (Disease Ontology) (3 alleles)
    Models Based on Experimental Evidence ( 2 )
    Modifiers Based on Experimental Evidence ( 2 )
    Allele
    Disease
    Interaction
    References
    Models Based on Experimental Evidence ( 1 )
    Allele
    Disease
    Evidence
    References
    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 (17)