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Rapid In Situ Hybridization using Oligonucleotide Probes on Paraformaldehyde-prefixed Brain of Rats with Serotonin Syndrome
Published on: September 23, 2015
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Disruptive mutations in the serotonin transporter associate serotonin dysfunction with treatment-resistant affective
Medrxiv : the Preprint Server for Health Sciences
|September 11, 2023
Summary
We identified two novel serotonin transporter (SERT) variants, SERT-N217S and SERT-A500T, in patients with treatment-resistant affective disorders. These variants cause partial loss-of-function, implicating SERT dysfunction in mood disorder risk.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Affective disorders are a major global health burden, with the serotonergic system as a key therapeutic target.
- The serotonin transporter (SERT) regulates serotonin neurotransmission, but its role in psychiatric disease pathogenesis is unclear.
- Identifying genetic variants in SERT could elucidate disease mechanisms and inform treatment strategies.
Approach:
- Screened a cohort of 144 patients with treatment-resistant chronic affective disorders for novel coding SERT variants.
- Genetically characterized identified variants (SERT-N217S, SERT-A500T) against population databases (GnomAD, healthy controls).
- Performed functional assays to investigate the molecular mechanisms and impact of these variants on SERT function and trafficking.
Key Points:
- Identified two novel coding SERT variants, SERT-N217S and SERT-A500T, significantly enriched in patients with treatment-resistant affective disorders.
- Both variants result in a partial loss-of-function phenotype, with SERT-A500T affecting catalytic activity and SERT-N217S causing a trafficking deficiency.
- The SERT-N217S trafficking defect is potentially treatable with the pharmacochaperone noribogaine.
Conclusions:
- This study presents the first disease-associated loss-of-function SERT variants.
- SERT dysfunction, due to these identified variants, is implicated as a risk factor for chronic affective disorders.
- Findings highlight the importance of the serotonergic system and SERT function in the etiology of mood disorders.
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