The human gene ASH1L has been identified as a susceptibility locus for the development of autism spectrum disorder (ASD). ASH1L encodes a histone-modifying member of the trithorax group of transcriptional activators. This model uses the single orthologous gene in Drosophila, ash1, 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.
Dmel\ash1 is orthologous to a second human gene, SETBP1. SETBP1 has also been implicated in the development of ASD; the SFARI Gene autism database rates the gene-autism association for both ASH1L and SETBP1 as high confidence (see below). Both ASH1L and SETBP1 are implicated in forms of autosomal dominant intellectual disability (MIM:617796, MIM:616078). Neither ASH1L nor SETBP1 has been introduced into flies.
Homozygous loss-of-function alleles of Dmel\ash1 are lethal in the larval or pupal stage; animals heterozygous for loss-of-function mutations do not exhibit detectable phenotypes. This model uses animals heterozygous for a loss-of-function mutation of ash1 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 exhibits second site non-complementation: assayed in the larval neuromuscular junction, failure of presynaptic homeostatic plasticity (PHP) is observed. 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 ash1 exhibit failure of presynaptic homeostatic plasticity.
The PHP phenotypes of different double heterozygous mutation combinations have been used to isolate and characterize genetic modifiers.
[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 (MIM: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 MIM:209850; 2017.03.18]
The SFARI Gene autism database (https://gene.sfari.org) rates the gene-autism association for ASH1L and SETBP1 as high confidence (score 1). [2020.11.01]
ASH1L encodes a histone lysine methyltransferase; it is a member of the trithorax group of transcriptional activators. [Gene Cards, ASH1L; 2020.11.03]
Many to one: 2 human genes to Drosophila gene; the human genes are ASH1L and SETBP1.
High-scoring ortholog of human ASH1L; low-scoring ortholog of human SETBP1 (1 Drosophila to 2 human). Dmel\ash1 shares shares 20-27% identity and 33-41% similarity with the human genes.
