Copy number variants (CNVs) affecting a number of different chromosomal regions have been implicated in the development of autism and schizophrenia. One such region, 16p11.2, includes approximately 25 genes, including mitogen-activated protein kinase 3 (MAPK3), which plays a key role in the MAPK/ERK kinase cascade. MAPK3 is also associated with schizophrenia and/or autism in several GWAS studies. There is a single high-scoring ortholog is Drosophila, rolled (Dmel\rl), for which an extensive number of mutations, including classical amorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\rl is also orthologous to the human gene MAPK1.
Several UAS constructs of the wild-type human Hsap\MAPK3 gene have been introduced into flies as part of a large-scale study of human synaptic genes.
In an RNAi-based screen of Drosophila genes orthologous to human genes within the 16p11.2 region, knockdown of Dmel\rl was observed to result in neuroanatomy defects in larval neuromuscular junctions, including multiple and ectopic innervations of presynaptic motor axons into postsynaptic body-wall muscles. A large number of physical and genetic interactions for Dmel\rl have been described; see below and in the rl gene report.
Genetic interactions of genes within the chromosome 16p11.2 deletion have been studied using the orthologous genes in flies (see FBhh0001068).
A number of genes in human have been implicated in both autism spectrum disorder and schizophrenia. Cases that have been studied in flies include NRXN1 (FBhh0000516), MAPK3 (this report), ABCA13 (FBhh0001047), and TAOK2 (FBhh0001219).
[updated Jul. 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]
MAPK3 is associated with schizophrenia and/or autism in several GWAS studies (see GWAS Catalog, below in 'External links').
The SFARI Gene autism database ( https:gene.sfari.org ) rates the gene-autism association for MAPK3 as suggestive evidence (score 3). [2020.11.05]
MAPK3 encodes a serine/threonine kinase that is a member of the MAP kinase family. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act in a signaling cascade that regulates various cellular processes such as proliferation, differentiation, and cell cycle progression in response to a variety of extracellular signals. MAPK1 (ERK2) and MAPK3 (ERK1) play key roles in this cascade. The activation of MAPK1 or MAPK3 kinase requires its phosphorylation by upstream kinases; upon activation, the MAP kinase translocates to the nucleus of the stimulated cells, where it phosphorylates nuclear targets. [Gene Cards, MAPK3, MAPK1; 2018.07.11]
High-scoring ortholog of human MAPK1 and MAPK3 (1 Drosophila to 2 human); multiple more distantly related genes in both species. Dmel\rl shares 76-82% identity and 84-90% similarity with the human genes.