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General Information
Name
age-dependent ectopic fat accumulation, HDAC6-related
FlyBase ID
FBhh0000707
Disease Ontology Term
Parent Disease
OMIM
Overview

A Drosophila model of age-dependent ectopic fat accumulation (EFA) has been developed based on the observation that lipid droplet accumulation and relative triglycerides levels change in some tissues in young vs. aged flies. These signs of EFA are observed primarily in the thorax, most noticeably in the jump muscle. In a screen of candidate genes involved in the protein folding-unfolding process or in the unfolding-degradation process, mutations of HDAC6 were identified as specifically modulating age-dependent EFA (phenotypes assessed in young flies vs. old flies).

Dmel\HDAC6, which shares its symbol with the closest ortholog in human, is a cytoplasmic histone deacetylase. HDACs of this type interact with many substrates other than histones, including cytoskeletal proteins and chaperone complex proteins. Dmel\HDAC6 is also closely related to human HDAC10. For Dmel\HDAC6, RNAi-targeting constructs, alleles caused by insertional mutagenesis, and alleles created by targeted recombination, including an amorphic allele, have been generated.

UAS constructs of the human Hsap\HDAC6 gene have been introduced into flies, including wild-type and a modified gene that is catalytically dead, however, they have not been used in the context of this human disease model.

Animals homozygous for an amorphic allele of Dmel\HDAC6 are viable and fertile. They exhibit lipid metabolism phenotypes such as significant age-dependent EFA, lipid composition imbalance, and reduced animal longevity on a high-fat diet. The EFA and longevity phenotypes are ameliorated by a reduction of Dmel\Lsd-2 (see the human disease model report 'obesity, susceptibility to (postulated), PLIN-related' FBhh0000497). It is postulated that transition to EFA depends on regulation of Lsd-2 by HDAC6.

Genetic and physical interactions have been described for Dmel\HDAC6; see the below and in HDAC6 gene report.

[updated Jan. 2018 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: age-dependent ectopic fat accumulation, HDAC6-related
OMIM report
Human gene(s) implicated
Symptoms and phenotype
Genetics
Cellular phenotype and pathology
The storage of triglyceride droplets in nonadipose tissues is termed ectopic fat storage (Snel et al., 2012; pubmed:22675355).
Molecular information
HDAC6 is a cytoplasmic, class IIb HDAC, known to interact with a number of cytoplasmic proteins, including tubulin and HSP90 (Yao and Yang, 2011; pubmed:21234400).
External links
Disease synonyms
ectopic fat storage, age-dependent
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)
Many to many: multiple in both species.
Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    Histone deacetylase 6 (HDAC6) encodes a cytosolic deacetylase that functions as a key modulator of proteostasis by mediating ubiquitin-proteasomal and lysosomal degradation of native and/or misfolded proteins. [Date last reviewed: 2018-09-27]
    Cellular component (GO)
    Gene Groups / Pathways
    Comments on ortholog(s)
    High-scoring ortholog of human HDAC6; moderate-scoring ortholog of HDAC10; lower-scoring orthologs in both species. Dmel\HDAC6 shares 33-37% identity and 47-51% similarity with human HDAC6 and HDAC10.
    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 (5 groups)
    RNA-protein
    Interacting group
    Assay
    References
    anti tag coimmunoprecipitation, primer specific pcr
    protein-protein
    Interacting group
    Assay
    References
    anti bait coimmunoprecipitation, western blot
    enzymatic study, autoradiography, anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based
    protein-protein
    Interacting group
    Assay
    References
    enzymatic study, western blot
    Alleles Reported to Model Human Disease (Disease Ontology) (7 alleles)
    Models Based on Experimental Evidence ( 0 )
    Allele
    Disease
    Evidence
    References
    Modifiers Based on Experimental Evidence ( 6 )
    Models Based on Experimental Evidence ( 0 )
    Allele
    Disease
    Evidence
    References
    Modifiers Based on Experimental Evidence ( 1 )
    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
    amorphic allele - molecular evidence
    ends-in gene targeting
    References (3)