Autism spectrum disorder associated with low serotonin in CSF and mutations in the SLC29A4 plasma membrane monoamine transporter (PMAT) gene

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.

Neurobehavioral effects of long‐term maternal fructose intake in rat offspring

“…In line with earlier studies, our study demonstrated that chronic intake of fructose throughout pregnancy and lactation has a profound impact on brain development by altering the expression of TNF-α and several neurodevelopmental biomarkers such as NRG1, GAD67, NGF and IGF1. Moreover, decreased levels of brain 5HIAA, end-metabolite of serotonin metabolism, in fructose-exposed groups confirmed the findings of previous studies that showed significantly lowered serotonin turnover in ASD patients (Adamsen et al, 2014;Sparks et al, 2014). Parallel to clinical observations, in an experimental study, it has been found that mice deficient in neuronal tryptophan hydroxylase 2 (Tph2-/-), which lack brain serotonin, displayed considerable deficits in social interaction and communication, and also showed highly repetitive and compulsive behaviors (Kane et al, 2012).…”

Annual Research Review: The state of autism intervention science: progress, target psychological and biological mechanisms and future prospects

“…The serotonergic system was one of the first neurotransmitter systems to be investigated in the pathophysiology of ASD. Several studies have reported elevated levels of platelet serotonin in a third of ASD samples (Cross et al., ); short‐term dietary depletion of serotonin is linked to increase repetitive behaviours and anxiety in ASD subjects (Veenstra‐Vanderweele et al., ); and mutations in serotonin transporter genes such as SLC29A4 have been linked to ASD symptoms (Adamsen et al., ). Neuroimaging studies using PET have shown significantly lower levels of serotonin synthesis in ASD children compared to controls (Chandana et al., ), particularly in medial frontal cortex, midbrain and temporal lobe areas (Makkonen, Riikonen, Kokki, Airaksinen, & Kuikka, ).…”

The plasma membrane monoamine transporter (PMAT): Structure, function, and role in organic cation disposition

“…In the CNS, dysregulation of monoamine neurotransmission is critically involved in a number of brain disorders, such as depression, autism, schizophrenia, Parkinson's disease, and drug addiction. Although a recent study in patients with autism spectrum disorder with altered CSF levels of 5-HT suggested a potential association with rare mutations in the PMAT (SLC29A4) gene, 55 little is currently known regarding the involvement of PMAT in monoamine-related brain disorders. If PMAT is proven to indeed regulate monoamine neurotransmission in vivo, there could be enormous clinical and therapeutic implications for this transporter.…”