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