Hyperserotonemia is the most replicated biochemical abnormality associated with autism spectrum disorders (ASD). However, previous studies of serotonin synthesis, catabolism, and transport have not elucidated the mechanisms underlying this hyperserotonemia. Here we investigated serotonin sulfation by phenol sulfotransferases (PST) in blood samples from 97 individuals with ASD and their first-degree relatives (138 parents and 56 siblings), compared with 106 controls. We report a deficient activity of both PST isoforms (M and P) in platelets from individuals with ASD (35% and 78% of patients, respectively), confirmed in autoptic tissues (9 pineal gland samples from individuals with ASD—an important source of serotonin). Platelet PST-M deficiency was strongly associated with hyperserotonemia in individuals with ASD. We then explore genetic or pharmacologic modulation of PST activities in mice: variations of PST activities were associated with marked variations of blood serotonin, demonstrating the influence of the sulfation pathway on serotonemia. We also conducted in 1645 individuals an extensive study of SULT1A genes, encoding PST and mapping at highly polymorphic 16p11.2 locus, which did not reveal an association between copy number or single nucleotide variations and PST activity, blood serotonin or the risk of ASD. In contrast, our broader assessment of sulfation metabolism in ASD showed impairments of other sulfation-related markers, including inorganic sulfate, heparan-sulfate, and heparin sulfate-sulfotransferase. Our study proposes for the first time a compelling mechanism for hyperserotonemia, in a context of global impairment of sulfation metabolism in ASD.

高血清素血症是与自闭症谱系障碍（ASD）相关的复制最多的生化异常。但是，先前有关血清素合成，分解代谢和转运的研究尚未阐明这种高血清素血症的潜在机制。在这里，我们调查了97名患有ASD的人及其一级亲属（138个父母和56个兄弟姐妹）的血液样本中苯酚磺基转移酶（PST）所致的5-羟色胺硫酸化，与106名对照进行了比较。我们报告了在自闭症组织（9个自发自闭症患者的重要来源的松果体样本）中证实的自闭症患者（分别为35％和78％的患者）的血小板中PST亚型（M和P）的活性不足。血清素）。血小板PST-M缺乏与ASD患者的高血清素血症密切相关。然后，我们探讨了小鼠PST活性的遗传或药理调节：PST活性的变化与血液中血清素的显着变化有关，表明硫酸化途径对血清素的影响。我们还对1645个人进行了广泛的研究，SULT1A基因编码PST，并定位在高度多态的16p11.2基因座上，该基因未揭示拷贝数或单核苷酸变异与PST活性，血清素或ASD风险之间的关联。相反，我们对ASD中硫酸盐代谢的更广泛评估显示，其他与硫酸盐有关的标志物也受损，包括无机硫酸盐，硫酸乙酰肝素和硫酸肝素硫酸盐转移酶。我们的研究首次提出了一种高血清素血症的引人注目的机制，这是在ASD中硫酸盐代谢的全球损害的背景下提出的。