Open Close
General Information
Name
Huntington disease
FlyBase ID
FBhh0000003
Disease Ontology Term
Parent Disease
Overview

This report describes Huntington disease (HD), an inherited neurodegenerative disease with a single causative gene; the disease is inherited as an autosomal dominant. Huntington disease was the first CAG-repeat disease for which the gene was identified and characterized molecularly. These diseases, largely neurodegenerative in nature, are 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. The human gene implicated in HD is Hsap\HTT, a widely expressed gene for which the function is not known. There is a single high-scoring fly ortholog, Dmel\htt, for which RNAi-targeting constructs and alleles caused by insertional mutagenesis have been generated; an amorphic genotype has been created and characterized.

UAS constructs of the human Hsap\HTT gene have been introduced into flies; heterologous rescue (functional complementation) has been demonstrated for the eye phenotype of an RNAi allele of Dmel\htt expressed in the adult eye (FBrf0207284). Hsap\HTT transgenes with CAG expansions expressed in the fly eye induce degeneration and death of adult photoreceptor neurons resulting in an easily scored and semi-quantitative phenotype, allowing detection of genetic interactions and screening of synthetic compounds.

Variant(s) implicated in human disease tested (as transgenic human gene, HTT): Q18_Q38 (CAG)n EXPANSION; UAS-HTT constructs with differing numbers of the pathological CAG repeat have been created. Pan-neuronal expression of pathological expansions results in progressive locomotor defects and neuroanatomy defects, including progressive degeneration of photoreceptor rhabdomeres in the eye. Expression in the developing eye only has been used to assess development of neuroanatomy defects.

Cardiomyopathy is observed at elevated rates among HD patients; uncontrolled weight loss is also frequently associated with the disease. These aspects of the disease have been investigated in flies. Cardiac-specific expression of pathogenic Hsap\HTT polyQ constructs has allowed cellular and molecular characterization of the resulting cardiac dysfunction. Hsap\HTT transgenes with CAG expansions expressed in the fat body result in weight loss in flies, despite higher food intake, and eventual death. In a study associating metabolic phenotypes with variants found in the Drosophila Genetic Reference Panel (DGRP) lines, Dmel\htt emerged as having a significant metabolic role. Assessment of htt knockdown flies revealed dramatic increases in body size and starvation resistance. These results in flies appear to support a mechanism involving a toxic gain-of-function in the mutant protein rather than a loss of wild-type HTT function for the uncontrolled weight loss associated with Huntington disease.

Animals with a null genotype for htt appear to develop normally into adulthood; as they age, they exhibit a progressive decline in mobility; they also have a shortened adult lifespan. (See above for loss-of-function metabolic phenotypes.) Physical and genetic interactions have been described for Dmel\htt; see below and in the gene report for htt.

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

[updated Jan. 2020 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: Huntington disease
OMIM report

[HUNTINGTON DISEASE; HD](https://omim.org/entry/143100)

Human gene(s) implicated

[HUNTINGTIN; HTT](https://omim.org/entry/613004)

Symptoms and phenotype

Huntington disease (HD) is a progressive neurodegenerative disorder with a distinct phenotype characterized by chorea [jerky, involuntary movements], dystonia [involuntary muscle contractions], incoordination, cognitive decline, and behavioral difficulties. (reviewed in Walker, 2007, pubmed:17240289) [from OMIM:143100; 2013.07.18]

Cardiomyopathy is observed at elevated rates among HD patients (Mielcarek, 2015; pubmed:26459693), as is weight loss and metabolic dysregulation (Lakra et al. 2019; FBrf0242929).

Genetics

Huntington disease is inherited as an autosomal dominant; it is caused by an expanded trinucleotide repeat (CAG)n, encoding glutamine, at the N terminus of the gene encoding huntingtin (HTT) (Huntington's Disease Collaborative Research Group, 1993, pubmed:8458085). In normal individuals the gene has 11 to 35 copies of the CAG repeat; when the number of CAG repeats reaches 41 or more, the disease is fully penetrant; incomplete penetrance can occur with 36 to 40 repeats. The number of repeats accounts for approximately 60% of the variation in age at onset, with the remainder determined by modifying genes and environment (Walker, 2007, pubmed:17240289). [from OMIM:143100 and OMIM:613004; 2013.07.18]

Alternative terms for polyglutamine disease: described as CAG repeat at nucleotide level; described as polyglutamine or polyQ at protein level.

The length of the CAG repeat accounts for about 50–70% of the overall variance in age of onset (longer repeat length correlated with earlier age of onset).

Cellular phenotype and pathology

At autopsy, sufferers of Huntington disease show progressive, selective neural cell loss and atrophy in distinct areas of the brain. [from OMIM:143100; 2013.07.18]

Molecular information

The HTT gene encodes huntingtin, a widely expressed protein of unknown function. The wide expression of the HTT transcript does not correlate with the pattern of neuropathology in the disease. [from OMIM:613004; 2013.07.18]

The huntingtin protein is required for human development and normal brain function. Some posttranslational modifications, such as phosphorylation, can play a significant role in regulating toxicity of the huntingtin protein. Pathogenesis of HD involves cleavage of the protein and is associated with neuronal accumulation of aggregated forms.

See descriptive summary for Huntington's disease in KEGG Disease Pathways (link below).

External links
Disease synonyms
Huntington chorea
Huntington disease
HD
Huntington's disease
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
Symbol / Name
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

One to one: 1 human to 1 Drosophila.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    huntingtin (htt) encodes a scaffold protein involved in mitotic spindle orientation, chromatin regulation and axonal transport. It is the ortholog of human HTT and has been manipulated to study Huntington's disease in flies. [Date last reviewed: 2019-06-13]
    Molecular function (GO)
      Cellular component (GO)
      Gene Groups / Pathways
        Comments on ortholog(s)

        Ortholog of human HTT (1 Drosophila to 1 human). Dmel\htt shares 20% identity and 34% similarity with human HTT (2 domains not in common).

        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 (3 groups)
        protein-protein
        Interacting group
        Assay
        References
        pull down, peptide massfingerprinting
        pull down, peptide massfingerprinting
        anti tag coimmunoprecipitation, western blot
        Alleles Reported to Model Human Disease (Disease Ontology) (39 alleles)
        Models Based on Experimental Evidence ( 3 )
        Modifiers Based on Experimental Evidence ( 4 )
        Models Based on Experimental Evidence ( 31 )
        Allele
        Disease
        Evidence
        References
        Modifiers Based on Experimental Evidence ( 22 )
        Allele
        Disease
        Interaction
        References
        is ameliorated by armG0192
        is ameliorated by wg1
        is ameliorated by wgSp-1
        is ameliorated by arm3
        is ameliorated by Wnt2O
        is exacerbated by sggUAS.cBa
        is ameliorated by Wnt2I
        is ameliorated by Wnt2RJ
        is ameliorated by pan3
        is exacerbated by sggS9A.UAS
        is ameliorated by pan2
        is ameliorated by Apc2UAS.cUa
        is ameliorated by AxnUAS.cUa
        is ameliorated by PfkUAS.cTa
        is ameliorated by ZwUAS.cLa
        is ameliorated by jpUAS
        is exacerbated by jpKK107921
        is ameliorated by Sirt117
        is exacerbated by Sirt117
        is ameliorated by htt81aa.UAS
        is ameliorated by cd1
        is ameliorated by cn3
        is ameliorated by vKK108195
        is ameliorated by v36f
        is exacerbated by htt98E2
        is ameliorated by BmcpUAS.cBa
        is exacerbated by ATP7GD3322
        is ameliorated by PsaUAS.cSa
        is exacerbated by Glut117J
        is exacerbated by Drp1UAS.cDa
        is NOT ameliorated by Gcn5UAS.cBa
        is exacerbated by Gcn5E333st
        is exacerbated by nej3
        is NOT exacerbated by mof2
        is NOT exacerbated by enok2
        is ameliorated by gEP514
        is ameliorated by MESR4EP386
        is exacerbated by TlEP1051
        is exacerbated by SNF4AγEP3015b
        is exacerbated by SNF4AγKG10152
        is ameliorated by mubEP3108
        is ameliorated by svrEP356
        is ameliorated by arm3
        is ameliorated by Khc8
        is exacerbated by Pgi2
        is ameliorated by pnutXP
        is exacerbated by shot3
        is exacerbated by PginNC1
        is exacerbated by fafBX4
        is ameliorated by Mef2X1
        is ameliorated by Chc1
        is ameliorated by arm2
        is ameliorated by DnaJ-1EP411
        is exacerbated by eff8
        is exacerbated by skdL7062
        is exacerbated by taraEP3463
        is exacerbated by cpoEP3378
        is ameliorated by pumbem
        is ameliorated by sovKG00226
        is ameliorated by 14-3-3εex4
        is exacerbated by Diap14
        is exacerbated by Akt104226
        is exacerbated by mubEP3623
        is exacerbated by vibEP651
        is exacerbated by vibEP513
        is exacerbated by sovEP1438
        is exacerbated by Sin3AdQ4
        is exacerbated by Sirt1EP2300
        is exacerbated by pumEP3461
        is ameliorated by solGD8164
        is ameliorated by SppLGD284
        is ameliorated by Mmp2BG00958
        is exacerbated by solEY02771
        is ameliorated by SppLEY06831
        is ameliorated by golGD3528
        is ameliorated by Mmp202353
        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
        FLPase
        amorphic allele - molecular evidence
        ends-in gene targeting
        References (229)