Decreased phenol sulfotransferase activities associated with hyperserotonemia in autism spectrum disorders.

Abstract

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.

• Authors: Cécile Pagan, Marion Benabou, Claire Leblond, Freddy Cliquet, Alexandre Mathieu, Nathalie Lemière, Hany Goubran-Botros, Richard Delorme, Marion Leboyer, Jacques Callebert, Thomas Bourgeron, Jean-Marie Launay
• Journal: Translational psychiatry (Transl Psychiatry) Vol. 11 Issue 1 Pg. 23 (01 07 2021) ISSN: 2158-3188 [Electronic] United States
• PMID: 33414449 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Serotonin
• Sulfotransferases
• Arylsulfotransferase

Topics

• Animals
• Arylsulfotransferase (genetics)
• Autism Spectrum Disorder (genetics)
• Humans
• Mice
• Serotonin
• Siblings
• Sulfotransferases (genetics)