Abstract
BackgroundPatients with autism spectrum disorder (ASD) may have low brain serotonin concentrations as reflected by the serotonin end-metabolite 5-hydroxyindolacetic acid (5HIAA) in cerebrospinal fluid (CSF).MethodsWe sequenced the candidate genes SLC6A4 (SERT), SLC29A4 (PMAT), and GCHFR (GFRP), followed by whole exome analysis.ResultsThe known heterozygous p.Gly56Ala mutation in the SLC6A4 gene was equally found in the ASD and control populations. Using a genetic candidate gene approach, we identified, in 8 patients of a cohort of 248 with ASD, a high prevalence (3.2%) of three novel heterozygous non-synonymous mutations within the SLC29A4 plasma membrane monoamine transporter (PMAT) gene, c.86A > G (p.Asp29Gly) in two patients, c.412G > A (p.Ala138Thr) in five patients, and c.978 T > G (p.Asp326Glu) in one patient. Genome analysis of unaffected parents confirmed that these PMAT mutations were not de novo but inherited mutations. Upon analyzing over 15,000 normal control chromosomes, only SLC29A4 c.86A > G was found in 23 alleles (0.14%), while neither c.412G > A (<0.007%) nor c.978 T > G (<0.007%) were observed in all chromosomes analyzed, emphasizing the rareness of the three alterations. Expression of mutations PMAT-p.Ala138Thr and p.Asp326Glu in cellulae revealed significant reduced transport uptake activity towards a variety of substrates including serotonin, dopamine, and 1-methyl-4-phenylpyridinium (MPP+), while mutation p.Asp29Gly had reduced transport activity only towards MPP+. At least two ASD subjects with either the PMAT-Ala138Thr or the PMAT-Asp326Glu mutation with altered serotonin transport activity had, besides low 5HIAA in CSF, elevated serotonin levels in blood and platelets. Moreover, whole exome sequencing revealed additional alterations in these two ASD patients in mainly serotonin-homeostasis genes compared to their non-affected family members.ConclusionsOur findings link mutations in SLC29A4 to the ASD population although not invariably to low brain serotonin. PMAT dysfunction is speculated to raise serotonin prenatally, exerting a negative feedback inhibition through serotonin receptors on development of serotonin networks and local serotonin synthesis. Exome sequencing of serotonin homeostasis genes in two families illustrated more insight in aberrant serotonin signaling in ASD.
Highlights
Patients with autism spectrum disorder (ASD) may have low brain serotonin concentrations as reflected by the serotonin end-metabolite 5-hydroxyindolacetic acid (5HIAA) in cerebrospinal fluid (CSF)
Developmental changes in brain serotonin synthesis capacity measured by PET using the radioactive marked serotonin precursor (α[11C]-methyl-L-tryptophan) showed a diminished capacity of whole-brain or regional brain serotonin synthesis in autistic children compared to non-autistic children, suggesting that developmental regulation of serotonin synthesis is involved in the pathogenesis of autism [14]. iii) Increased repetitive behaviors and irritability were observed in autistic patients when subjected to a dietary depletion of the serotonin precursor tryptophan due to an expected reduction in extracellular serotonin availability [15]
We found that isolated low brain serotonin concentration, as reflected by the 5HIAA in the CSF, is associated with pervasive developmental disorder – not otherwise specified (PDD-NOS) and the functional c.167G > C (p.G56A) mutation of the serotonin re-uptake transporter gene (SERT/SCL6A4) combined with a homozygous long (L/L) serotonin transporter (SERT) genelinked polymorphic promoter (5-HTTLPR) region [21]
Summary
Patients with autism spectrum disorder (ASD) may have low brain serotonin concentrations as reflected by the serotonin end-metabolite 5-hydroxyindolacetic acid (5HIAA) in cerebrospinal fluid (CSF). Iii) Increased repetitive behaviors and irritability were observed in autistic patients when subjected to a dietary depletion of the serotonin precursor tryptophan due to an expected reduction in extracellular serotonin availability [15]. Increased extracellular serotonin availability due to administration of selective serotonin re-uptake inhibitors led to reduced symptoms of irritability and rigid-compulsive behavior in individuals with ASD [15,17]. These findings emphasize that abnormal serotonergic transmission may be important in the pathogenesis of autism [18,19]. Due to the serotonin hypothesis of autism, genes encoding proteins involved in brain serotonin metabolism and neurotransmission have received more attention than other categories of genes [20]
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