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