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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
HD
Huntington's disease
Huntington chorea
Huntington 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
        Other Genes Used: Viral, Bacterial, Synthetic (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) (52 alleles)
          Models Based on Experimental Evidence ( 3 )
          Modifiers Based on Experimental Evidence ( 4 )
          Models Based on Experimental Evidence ( 42 )
          Allele
          Disease
          Evidence
          References
          Modifiers Based on Experimental Evidence ( 33 )
          Allele
          Disease
          Interaction
          References
          is ameliorated by armG0192
          is ameliorated by wg1
          is ameliorated by wgSp-1
          is ameliorated by Wnt2O
          is ameliorated by arm3
          is ameliorated by Wnt2I
          is ameliorated by Wnt2RJ
          is exacerbated by sggUAS.cBa
          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 ZwUAS.cLa
          is ameliorated by PfkUAS.cTa
          is exacerbated by jpKK107921
          is ameliorated by jpUAS
          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 v36f
          is exacerbated by Drp1UAS.cDa
          is exacerbated by Glut117J
          is ameliorated by gEP514
          is ameliorated by svrEP356
          is ameliorated by MESR4EP386
          is exacerbated by TlEP1051
          is exacerbated by SNF4AγEP3015b
          is exacerbated by SNF4AγKG10152
          is ameliorated by mubEP3108
          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 arm3
          is ameliorated by Khc8
          is exacerbated by Pgi2
          is ameliorated by pnutXP
          is exacerbated by shot3
          is exacerbated by fafBX4
          is exacerbated by PginNC1
          is ameliorated by Mef2X1
          is ameliorated by Chc1
          is ameliorated by arm2
          is exacerbated by skdL7062
          is exacerbated by eff8
          is ameliorated by DnaJ-1EP411
          is exacerbated by taraEP3463
          is exacerbated by cpoEP3378
          is ameliorated by pumbem
          is ameliorated by sovKG00226
          is exacerbated by Sin3AdQ4
          is exacerbated by Sirt1EP2300
          is exacerbated by pumEP3461
          is ameliorated by 14-3-3εex4
          is exacerbated by Diap14
          is exacerbated by Akt04226
          is exacerbated by mubEP3623
          is exacerbated by vibEP651
          is exacerbated by vibEP513
          is exacerbated by sovEP1438
          is ameliorated by solGD8164
          is ameliorated by SppLGD284
          is ameliorated by Mmp2BG00958
          is ameliorated by golGD3528
          is ameliorated by Mmp202353
          is exacerbated by solEY02771
          is ameliorated by SppLEY06831
          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
          FLPase
          amorphic allele - molecular evidence
          ends-in gene targeting
          References (281)