Enhanced activity of human serotonin transporter variants associated with autism

Rare, functional, non-synonymous variants in the human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT) gene (SLC6A4) have been identified in both autism and obsessive-compulsive disorder (OCD). Within autism, rare hSERT coding variants associate with rigid-compulsive traits, suggesting bot...

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Bibliographic Details
Published in:Philosophical transactions of the Royal Society of London. Series B. Biological sciences 2009-01, Vol.364 (1514), p.163-173
Main Authors: Prasad, Harish C, Steiner, Jennifer A, Sutcliffe, James S, Blakely, Randy D
Format: Article
Language:English
Subjects:
Alleles
Animals
Autism
Autistic disorder
Autistic Disorder - genetics
Autistic Disorder - metabolism
CHO Cells
Cricetinae
Cricetulus
Cyclic GMP-Dependent Protein Kinases - metabolism
Gene expression regulation
Gene Expression Regulation - genetics
Gene Expression Regulation - physiology
Genetic Variation
Genetics
Glutamic Acid - metabolism
HeLa cells
HeLa Cells - metabolism
Humans
Kinase
Lymphocytes
Lymphocytes - metabolism
Neurons
p38 Mitogen-Activated Protein Kinases - metabolism
Phosphatase
Phosphorylation
Serotonin
Serotonin - metabolism
Serotonin plasma membrane transport proteins
Serotonin Plasma Membrane Transport Proteins - genetics
Serotonin Plasma Membrane Transport Proteins - metabolism
Serotonin receptors
Transporter
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Summary:Rare, functional, non-synonymous variants in the human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT) gene (SLC6A4) have been identified in both autism and obsessive-compulsive disorder (OCD). Within autism, rare hSERT coding variants associate with rigid-compulsive traits, suggesting both phenotypic overlap with OCD and a shared relationship with disrupted 5-HT signalling. Here, we document functional perturbations of three of these variants: Ile425Leu; Phe465Leu; and Leu550Val. In transiently transfected HeLa cells, the three variants confer a gain of 5-HT transport phenotype. Specifically, enhanced SERT activity was also observed in lymphoblastoid lines derived from mutation carriers. In contrast to previously characterized Gly56Ala, where increased transport activity derives from catalytic activation, the three novel variants exhibit elevated surface density as revealed through both surface antagonist-binding and biotinylation studies. Unlike Gly56Ala, mutants Ile425Leu, Phe465Leu and Leu550Val retain a capacity for acute PKG and p38 MAPK regulation. However, both Gly56Ala and Ile425Leu demonstrate markedly reduced sensitivity to PP2A antagonists, suggesting that deficits in trafficking and catalytic modulation may derive from a common basis in perturbed phosphatase regulation. When expressed stably from the same genomic locus in CHO cells, both Gly56Ala and Ile425Leu display catalytic activation, accompanied by a striking loss of SERT protein.
ISSN:0962-8436
1471-2970
DOI:10.1098/rstb.2008.0143