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General Information
Name
autism spectrum disorder, susceptibility to, WDFY3,4-related
FlyBase ID
FBhh0001279
OMIM
Overview

The human gene WDFY3 has been identified as a susceptibility locus for the development of autism spectrum disorder (ASD). WDFY3 encodes a protein that plays an essential role in macroautophagy-mediated clearance of the aggregated proteins; it also plays a role in normal brain development. This model uses the single orthologous gene in Drosophila, bchs, for which for which a variety of genetic reagents have been generated, including loss-of-functions mutations, RNAi targeting constructs, and alleles caused by insertional mutagenesis.

Human WDFY3 is also implicated in a form of autosomal dominant microcephaly (MCPH18; see FBhh0000610). Multiple UAS constructs of the human Hsap\WDFY3 gene have been introduced into flies and characterized in the context of this disease.

Dmel\bchs is orthologous to a second human gene, WDFY4. WDFY4 may also be associated with ASD; it is described as a 'strong candidate' by SFARI Gene (see below). Human WDFY4 has not been introduced into flies.

Animals homozygous for loss-of-function alleles of Dmel\bchs survive to adulthood but have a shortened adult life-span and exhibit progressive neuronal phenotypes; animals heterozygous for loss-of-function mutations do not exhibit detectable phenotypes. This model uses animals heterozygous for a loss-of-function mutation of bchs and also heterozygous for a mutation in a second Drosophila gene orthologous to a human gene associated with ASD susceptibility, Rim (see FBhh0001277). This genetic combination does not exhibit second site non-complementation: assayed in the larval neuromuscular junction, normal presynaptic homeostatic plasticity (PHP) is observed. However, during testing of deficiencies for candidate genes that impact PHP using the same assumption of second site non-complementation, several deficiencies plus a heterozygous loss-of-function mutation of bchs exhibit failure of presynaptic homeostatic plasticity.

[updated Nov. 2020 by FlyBase; FBrf0222196]

Disease Summary Information
Parent Disease Summary: autism spectrum disorder, susceptibility to
Symptoms and phenotype

Autism, the prototypic pervasive developmental disorder (PDD), is usually apparent by 3 years of age. It is characterized by a triad of limited or absent verbal communication, a lack of reciprocal social interaction or responsiveness, and restricted, stereotypic, and ritualized patterns of interests and behavior (Bailey et al., 1996, pubmed:8655659; Risch et al., 1999, pubmed:10417292). 'Autism spectrum disorder,' sometimes referred to as ASD, is a broader phenotype encompassing the less severe disorders Asperger syndrome (OMIM:608638) and pervasive developmental disorder, not otherwise specified (PDD-NOS). 'Broad autism phenotype' includes individuals with some symptoms of autism, but who do not meet the full criteria for autism or other disorders. Mental retardation coexists in approximately two-thirds of individuals with ASD, except for Asperger syndrome, in which mental retardation is conspicuously absent (Jones et al., 2008; pubmed:18698615). [from OMIM:209850; 2017.03.18]

Specific Disease Summary: autism spectrum disorder, susceptibility to, WDFY3,4-related
OMIM report
Human gene(s) implicated
Symptoms and phenotype
Genetics

The SFARI Gene autism database (https://gene.sfari.org) rates the gene-autism association for WDFY3 as high confidence (score 1). The SFARI Gene autism database rates the gene-autism association for WDFY4 as 'strong candidate' (score 2). [2020.11.01]

Cellular phenotype and pathology
Molecular information

WDFY3 encodes a phosphatidylinositol 3-phosphate-binding protein that is required for aggregate clearance by autophagy. The WDFY3 protein shuttles from the nuclear membrane to colocalize with aggregated proteins, where it complexes with other autophagic components to achieve macroautophagy-mediated clearance of the aggregated proteins. WDFY3 also plays important roles in normal brain development and the formation of axonal tracts in the CNS. [Gene Cards, WDFY3; 2020.11.03]

External links
Disease synonyms
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to one: 2 human genes to 1 Drosophila gene; the human genes are WDFY3 and WDFY4.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    blue cheese (bchs) is a neuronally expressed gene that encodes a member of the BEACH (Beige and Chediak-Higashi)-domain superfamily, whose members are involved in vesicle trafficking. It antagonizes the activity of the product of Rab11. It serves as a scaffold for autophagy proteins, and contributes to ref(2)P-mediated aggrephagy. It contributes to nervous system development, lysosome transport and sphingolipid metabolism. [Date last reviewed: 2018-11-08]
    Molecular function (GO)
    Gene Groups / Pathways
      Comments on ortholog(s)

      High-scoring ortholog of human WDFY3; moderate-scoring ortholog of WDFY4 (1 Drosophila to 2 human). Dmel\bchs shares 47% identity, 63% similarity with WDFY3 and 30% identity, 48% similarity with WDFY4.

      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 (0 groups)
        Alleles Reported to Model Human Disease (Disease Ontology) (3 alleles)
        Models Based on Experimental Evidence ( 1 )
        Allele
        Disease
        Evidence
        References
        Modifiers Based on Experimental Evidence ( 2 )
        Models Based on Experimental Evidence ( 1 )
        Allele
        Disease
        Evidence
        References
        Modifiers Based on Experimental Evidence ( 0 )
        Allele
        Disease
        Interaction
        References
        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
        loss of function allele
        ethyl methanesulfonate
        loss of function allele
        ethyl methanesulfonate
        References (3)