The human genes SCL9A9 and SCL9A6 have been identified as candidate susceptibility loci for autism spectrum disorder (see MIM:613410, AUTS16, FBhh0001282). Each gene encodes a Na+/H+ antiporter that is part of the monovalent cation proton antiporter (CPA) superfamily. There is a single high-ranking ortholog of SLC9A6 and SLC9A9 in Drosophila, Nhe3. Multiple alleles have been generated for Nhe3, including a fluorescently tagged protein construct, multiple RNAi targeting constructs, and insertion alleles.
Dmel\Nhe3 is also orthologous to human SLC9A7. None of the human genes, SLC9A6, SLC9A7, or SLC9A9, has been introduced into flies. SLC9A6 is also implicated in a syndromic form of intellectual disability (MIM:300243).
Drosophila Nhe3 loss-of-function mutants are viable, but show less response to visual stimuli, suggesting an impairment of post-photoreceptor neural structures. These electrophysiological visual responses to steady-state stimulation are similar to the response pattern in human adults with autism spectrum disorder, as well as that of a large sample of neurotypical individuals with high numbers of autistic traits.
[updated Jan. 2021 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]
Several mutations in the susceptibility to autism-16 (AUTS16 locus) region identified in autistic individuals have been mapped to SLC9A9. Additional clinical presentations that SLC9A9 mutations have proposed to affect include attention deficit hyperactivity disorder (ADHD), addiction, Alzheimers disease, and multiple sclerosis. (Kondapalli et al. 2014 and citations therein, pubmed:25002837).
The human Na+/H+ exchangers are encoded by the SLC9 gene family of the Solute Carrier (SLC) classification of transporters and are a subgroup of the eukaryotic and prokaryotic monovalent cation proton antiporter (CPA) superfamily. The SLC9A subfamily of Na+/H+ antiporters encodes nine family member paralogs in the human genome, SLC9A1-9. (Adapted from Donowitz et al. 2013, pubmed: 23506868.)
The SFARI Gene autism database ( https:gene.sfari.org ) rates the gene-autism associations for SLC9A6 as high confidence (score 1); for SLC9A6 as suggestive evidence (score 3). [2020.11.05]
In general, plasma membrane NHE isoforms regulate cytoplasmic pH, whereas intracellular isoforms primarily act at the compartmental lumen. Plasma membrane NHE function by coupling to the Na+ electrochemical gradient established by the ubiquitous sodium pump, moving Na+ ions into the cytoplasm in exchange for removal of H+. Thus, apically localized Na+/H+ exchangers, like SLC9A3, are important in sodium reabsorption in the kidney and gut. In contrast, active transport by endosomal NHE is driven by the H+ gradient generated by the V-type H+-ATPase, resulting in cation (Na+ or K+) sequestration coupled to removal of protons from the compartmental lumen. In this way, eNHE activity modulates pH within endosomes and various secretory organelles, which has been linked to cargo processing, turnover and trafficking. (Adapted from Kondapalli et al. 2014, pubmed:25002837.)
Many to one: 3 human paralogs to one Drosophila gene.
High-ranking ortholog of human SLC9A9. Nhe3 shares orthology with three similar paralogs in humans: SLC9A6, SLC9A7, and SLC9A9.
