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FB2026_01
,
released March 12, 2026
Three of the human KDM5 histone demethylases (KDM5A, KDM5B, and KDM5C) have been identified as potential susceptibility loci for autism spectrum disorder (ASD; FBhh000514). There is a high-ranking ortholog for KDM5 genes in Drosophila, Kdm5, for which an amorphic allele, RNAi targeting lines, overexpression constructs, and alleles created by insertional mutagenesis have been generated. KDM5C and KDM5B have also been implicated in forms of intellectual disability (MIM:300534, MIM:618109), one of which has been modeled in flies using a mutation in Kdm5 analogous to a known disease-implicated variant (FBhh0000849).
None of the human KDM5 genes has been introduced into flies.
Kdm5 hypomorphs show ASD-like social behaviors, including a decrease in social interactions. Interestingly, Kdm5 hypomorphs also show defects in the gut, which may influence behavioral phenotypes. Several gut dysfunction phenotypes are seen in Kdm5 mutants: the gut epithelial barrier is disrupted, food remains in the gut lumen longer, and there is a higher rate of intestinal stem-cell division. Sampling the gut flora finds a higher density of bacteria, but a smaller variety of species. Treating Kdm5 hypomorphs with antibiotics or with Lactobacillus plantarum improved both gut function and social behavior phenotypes. In Kdm5 hypomorphs and in Kdm5-knockdown S2 cells, several members of the IMD pathway (FBgg0001194) show elevated expression. Knocking down imd in Kdm5 mutants also improves social behaviors and gut defects, including the microbiome composition.
[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]
Immune dysregulation and gastrointestinal disturbances are of particular interest in light of numerous studies reporting ASD-associated abnormalities in the peripheral, enteric and neuro-immune system. Parallel studies reveal greater prevalence of gastrointestinal disorders and disturbances in ASD populations compared to controls. Co-morbid gastrointestinal symptoms in subsets of ASD individuals include diarrhea/constipation, abdominal pain and gastric reflux. Deficient integrity of the gut epithelium and increased intestinal permeability are also reported. (Vuong & Hsiao 2017 and references therein, pubmed:27773355.)
The body of research identifying genetic deletions and duplications, inherited and de novo, and rare and common variants in ASD is expansive. Evidence for genetic variants in the etiology of ASD includes genes involved in intellectual disability and neuropsychiatric disorders, common pathway genes and ASD-risk genes, multigenic contributions from rare or common variations, DNA mutations, and environmental effects on gene expression and/or protein function. Rare genetic risk factors, including those resulting in ASD-related syndromes (e.g. Fragile X), chromosomal abnormalities, and penetrant genes are estimated to contribute to ~20% of ASDs. At least 5% of non-syndromic, idiopathic, and primarily simplex ASD are caused by de novo copy-number variants. It is estimated that 400-1000 genes are likely to lead to a susceptibility to autism. (Masi et al. 2017 and references therein, pubmed:28213805.)
The SFARI Gene autism database ( https:gene.sfari.org ) rates the gene-autism associations for KDM5B as high confidence (score 1); for KDM5C as strong candidate (score 2). [2020.11.05]
The KDM5 demethylase subfamily belongs to the Jumonji C (JmjC) KDMs. These enzymes are 2-oxoglutarate-dependent dioxygenases which require for their function Fe2+ and oxygen in order to undergo the hydroxylation necessary to remove methyl groups. Members of the KDM5 subfamily are capable of removing tri- and dimethyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, their effect on transcription can be either activating or repressing. (Adapted from Plch et al. 2019 and references therein, pubmed:30246379.)
Many to one: 4 human genes to 1 Drosophila gene.
Many to one: 4 human genes to 1 Drosophila gene.
Many to one: 4 human genes to 1 Drosophila gene.
Many to one: 4 human genes to 1 Drosophila gene.
lid shares orthology with four human genes: KMD5A, KDM5B, KDM5C, and KDM5D, with KDM5A being the most highly-ranked ortholog in DIOPT version 8.0.