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Heterozygous mutations in GTP-cyclohydrolase-1 reduce BH4 biosynthesis but not pain sensitivity

Nasser, Arafata,b; Møller, Anette Torvinc; Hellmund, Vibec; Thorborg, Sidsel Sallinga; Jespersgaard, Cathrinea; Bjerrum, Ole J.b; Dupont, Erikd; Nachman, Göstae; Lykkesfeldt, Jensf; Jensen, Troels Staehelinc; Møller, Lisbeth Birka,g,*

doi: 10.1097/j.pain.0000000000001175
Research Paper
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Human studies have demonstrated a correlation between noncoding polymorphisms of “the pain protective” haplotype in the GCH1 gene that encodes for GTP cyclohydrolase I (GTPCH1)—which leads to reduced tetrahydrobiopterin (BH4) production in cell systems—and a diminished perception of experimental and clinical pain. Here, we investigate whether heterozygous mutations in the GCH1 gene which lead to a profound BH4 reduction in patients with dopa-responsive dystonia (DRD) have any effect on pain sensitivity. The study includes an investigation of GCH1-associated biomarkers and pain sensitivity in a cohort of 22 patients with DRD and 36 controls. The patients with DRD had, when compared with controls, significantly reduced levels of BH4, neopterin, biopterin, and GTPCH1 in their urine, blood, or cytokine-stimulated fibroblasts, but their pain response with respect to non-painful stimulation, (acute) stimulus-evoked pain, or pain response after capsaicin-induced sensitization was not significantly different. A family-specific cohort of 11 patients with DRD and 11 controls were included in this study. The patients with DRD were heterozygous for the pain protective haplotype in cis with the GCH1 disease-causing mutation, c.899T>C. No effect on pain perception was observed for this combined haplotype. In conclusion, a reduced concentration of BH4 is not sufficient to alter ongoing pain sensitivity or evoked pain responses.

Reduced concentration of BH4 in patients with dopa-responsive dystonia, because of GCH1 mutations, is not sufficient to alter ongoing pain sensitivity or evoked pain responses.

aApplied Human Molecular Genetics, Clinical Genetic Clinic, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark

bDepartment of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen Ø, Denmark

cDepartment of Neurology, Danish Pain Research Center, Aarhus University Hospital, Århus, Denmark

dDepartment of Neurology, Aarhus University Hospital, Århus, Denmark

eDepartment of Biology, Section of Ecology and Evolution, University of Copenhagen, Copenhagen Ø, Denmark

fDepartment of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark

gDepartment of Science and Environment, Roskilde University, Roskilde, Denmark

Corresponding author. Address: Applied Human Molecular Genetics, Kennedy Center, Clinical Genetic Clinic, Copenhagen University Hospital, Rigshospitalet, Gl. Landevej 7, Glostrup 2600, Denmark. Tel.: +4543260100; fax: +4543431130. E-mail address: lisbeth.birk.moeller@regionh.dk (L.B. Møller).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com).

Received July 25, 2017

Received in revised form January 19, 2018

Accepted January 29, 2018

© 2018 International Association for the Study of Pain
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