Abstract
Alterations in peripheral and central indices of serotonin (5-hydroxytryptamine, 5-HT) production, storage and signaling have long been associated with autism. The 5-HT transporter gene (HTT, SERT, SLC6A4) has received considerable attention as a potential risk locus for autism-spectrum disorders, as well as disorders with overlapping symptoms, including obsessive-compulsive disorder (OCD). Here, we review our efforts to characterize rare, nonsynonymous polymorphisms in SERT derived from multiplex pedigrees carrying diagnoses of autism and OCD and present the initial stages of our effort to model one of these variants, Gly56Ala, in vivo. We generated a targeting vector to produce the Gly56Ala substitution in the Slc6a4 locus by homologous recombination. Following removal of a neomycin resistance selection cassette, animals exhibiting germline transmission of the Ala56 variant were bred to establish a breeding colony on a 129S6 background, suitable for initial evaluation of biochemical, physiological and behavioral alterations relative to SERT Gly56 (wildtype) animals. SERT Ala56 mice were achieved and exhibit a normal pattern of transmission. The initial growth and gross morphology of these animals is comparable to wildtype littermate controls. The SERT Ala56 variant can be propagated in 129S6 mice without apparent disruption of fertility and growth. We discuss both the opportunities and challenges that await the physiological/behavioral analysis of Gly56Ala transgenic mice, with particular reference to modeling autism-associated traits.
Highlights
The serotonin system is implicated in autismElevated whole blood serotonin (5-hydroxytryptamine, 5HT) was first reported in autism by the lab of Daniel X
Follow-up linkage studies [48,49,50] have detected more significant evidence for linkage in this region when considering families with two or more affected male children and no affected females. These findings suggest that SERT might harbor sex-specific risk alleles for autism and possibly contribute to, or be responsive to, the gender bias of autism
PKC, PKG and p38 MAPK activators distinguish among SERT variants, phosphatase 2A (PP2A) antagonist sensitivity appears to be lost for both Ala56 and Leu425, two variants that represent the two distinct classes of regulatory defects observed in SERT variants. These findings indicate that altered PP2A interactions or SERT dephosphorylation may be a more fundamental alteration that extends across all variants, with secondary effects linked to the physical site of mutations
Summary
Elevated whole blood serotonin (5-hydroxytryptamine, 5HT) was first reported in autism by the lab of Daniel X. Carneiro and colleagues subsequently demonstrated physical and functional interactions between the ITGB3 and SERT proteins that regulates both platelet 5-HT uptake and aggregation [26] Consistent with these findings, three studies have reported a gene-gene interaction between ITGB3 and SLC6A4 in association with autism [34,35,36], supporting the idea that whole blood 5-HT represents a genetically-determined, intermediate phenotype in autism that can be mined for elucidation of disease susceptibility genes. In comparison to the reference hSERT cDNA (often termed “wild-type”) originally identified by Ramamoorthy and colleagues [76], both Ala and Asn605 demonstrated elevated 5-HT transport activity in transfected HeLa cells [72] This gain-offunction transport property was shared (and even exceeded) by several other SERT coding variants including Ile425Val, a variant reported by Ozaki and colleagues in association with two pedigrees bearing a complex neuropsychiatric phenotype including OCD, autism spectrum disorder, social phobia, and alcohol abuse [77]. As we have discussed elsewhere [71], the Kilic studies utilized an overexpression system
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