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Ann Neurol. 2019 Jun 8. doi: 10.1002/ana.25521. [Epub ahead of print]

A functional substitution in the L-aromatic amino acid decarboxylase enzyme worsens somatic symptoms via a serotonergic pathway.

Author information

1
The Alan Edwards Centre for Research on Pain, McGill University, Montréal, Qc, Canada.
2
Département de Biochimie, Centre Robert-Cedergren en Bioinformatique & Génomique, Université de Montréal, Montréal, Qc, Canada.
3
The Dr. John and Anne Chong Laboratory for Functional Genomics, Charles Perkins Centre and School of Life & Environt Sciences, the University of Sydney NSW 2006, Australia.
4
School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP, UK.
5
Center for Translational Pain Medicine, Department of Anesthesia, Duke University Medical Center, Durham, NC, USA.
6
National center for complementary and integrative health (NCCIH), National Health Institute (NIH), Bethesda, MD, USA.
7
Department of Dental Ecology, school of dentistry, University of North Carolina Chapel Hill, Chapel Hill, NC, USA.
8
UF Pain Research and Intervention Center of Excellence, College of Dentistry, University of Florida, Gainesville, FL, USA.
9
Department of Neural and Pain Sciences, Brotman Facial Pain Clinic, School of Dentistry, University of Maryland, Baltimore, MD, USA.
10
Department of Oral Diagnostic Services, University at Buffalo, Buffalo, New York, USA.

Abstract

OBJECTIVE:

Heightened somatic symptoms are reported by a wide range of patients with chronic pain and have been associated with emotional distress and physical dysfunction. Despite their clinical significance, molecular mechanisms leading to their manifestation are not understood.

METHODS:

We used an association study design based on a curated list of 3,295 SNPs mapped to 358 genes to test somatic symptoms reporting using the Pennebaker Inventory of Limbic Languidness (PILL) questionnaire from a case-control cohort of orofacial pain (n=1,607). A replication meta-analysis of three independent cohorts (n=3,189) was followed by functional validation, including in silico molecular dynamics, in vitro enzyme assays, and measures of serotonin (5-HT) plasma concentration.

RESULTS:

An association with T allele of rs11575542 coding for an arginine to glutamine substitution in the L-aromatic amino acid decarboxylase (AADC) enzyme was replicated in a meta-analysis of three independent cohorts. In a combined meta-analysis of all cohorts this association reached p=6.43x10-8 . In silico studies demonstrated that this substitution dramatically reduces the conformational dynamics of AADC, potentially lowering its binding capacity to a co-factor. In vitro enzymatic assays showed that this substitution reduces the maximum kinetic velocity of AADC, hence lowering serotonin (5-HT) levels. Finally, plasma samples from 90 subjects showed correlation between low 5-HT levels and heightened somatic symptoms.

INTERPRETATION:

Thus, using functional genomics approaches, we identified a polymorphism in AADC enzyme that contributes to somatic symptoms through reduced levels of 5-HT. Our findings suggest a molecular mechanism underlying the pathophysiology of somatic symptoms and opens up new treatment options targeting the serotonergic system. This article is protected by copyright. All rights reserved.

KEYWORDS:

L-aromatic amino acid decarboxylase; Pennebaker Inventory of Limbic Languidness; dopa decarboxylase; functional genomics; serotonin; somatic symptoms

PMID:
31177555
DOI:
10.1002/ana.25521

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