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Ann Neurol. 2019 Aug;86(2):168-180. doi: 10.1002/ana.25521. Epub 2019 Jun 8.

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

Author information

1
Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada.
2
Department of Biochemistry, Robert Cedergren Centre on Bioinformatics and Genomics, University of Montreal, Montreal, Quebec, Canada.
3
Dr John and Anne Chong Laboratory for Functional Genomics, Charles Perkins Centre and School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales, Australia.
4
School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom.
5
Department of Anesthesia, Center for Translational Pain Medicine, Duke University Medical Center, Durham, NC.
6
National Center for Complementary and Integrative Health, National Institutes of Health, Bethesda, MD.
7
Department of Dental Ecology, School of Dentistry, University of North Carolina Chapel Hill, Chapel Hill, NC.
8
University of Florida Pain Research and Intervention Center of Excellence, College of Dentistry, University of Florida, Gainesville, FL.
9
Department of Neural and Pain Sciences, Brotman Facial Pain Clinic, School of Dentistry, University of Maryland, Baltimore, MD.
10
Department of Oral Diagnostic Services, University at Buffalo, Buffalo, NY.

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 single nucleotide polymorphisms mapped to 358 genes to test somatic symptoms reporting using the Pennebaker Inventory of Limbic Languidness questionnaire from a case-control cohort of orofacial pain (n = 1,607). A replication meta-analysis of 3 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 the 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 3 independent cohorts. In a combined meta-analysis of all cohorts, this association reached p = 6.43 × 10-8 . In silico studies demonstrated that this substitution dramatically reduces the conformational dynamics of AADC, potentially lowering its binding capacity to a cofactor. in vitro enzymatic assays showed that this substitution reduces the maximum kinetic velocity of AADC, hence lowering 5-HT levels. Finally, plasma samples from 90 subjects showed correlation between low 5-HT levels and heightened somatic symptoms.

INTERPRETATION:

Using functional genomics approaches, we identified a polymorphism in the 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. ANN NEUROL 2019;86:168-180.

PMID:
31177555
DOI:
10.1002/ana.25521

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