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

Arafat Nasser, Anette Møller, Vibe Hellmund, Sidsel Salling Thorborg, Cathrine Jespersgaard, Ole Jannik Bjerrum, Erik Dupont, Gösta Nachman, Jens Lykkesfeldt, Troels Jensen, Lisbeth Birk Møller

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

    Resumé

    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.
    OriginalsprogEngelsk
    TidsskriftPain
    Vol/bind159
    Udgave nummer6
    Sider (fra-til)1012-1024
    ISSN0304-3959
    DOI
    StatusUdgivet - 2018

    Citer dette

    Nasser, A., Møller, A., Hellmund, V., Thorborg, S. S., Jespersgaard, C., Bjerrum, O. J., ... Møller, L. B. (2018). Heterozygous mutations in GTP-cyclohydrolase-1 reduce BH4 biosynthesis but not pain sensitivity. Pain, 159(6), 1012-1024. https://doi.org/10.1097/j.pain.0000000000001175
    Nasser, Arafat ; Møller, Anette ; Hellmund, Vibe ; Thorborg, Sidsel Salling ; Jespersgaard, Cathrine ; Bjerrum, Ole Jannik ; Dupont, Erik ; Nachman, Gösta ; Lykkesfeldt, Jens ; Jensen, Troels ; Møller, Lisbeth Birk. / Heterozygous mutations in GTP-cyclohydrolase-1 reduce BH4 biosynthesis but not pain sensitivity. I: Pain. 2018 ; Bind 159, Nr. 6. s. 1012-1024.
    @article{93ce35b7f8f54c51816bc2cc0ce44538,
    title = "Heterozygous mutations in GTP-cyclohydrolase-1 reduce BH4 biosynthesis but not pain sensitivity",
    abstract = "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.",
    author = "Arafat Nasser and Anette M{\o}ller and Vibe Hellmund and Thorborg, {Sidsel Salling} and Cathrine Jespersgaard and Bjerrum, {Ole Jannik} and Erik Dupont and G{\"o}sta Nachman and Jens Lykkesfeldt and Troels Jensen and M{\o}ller, {Lisbeth Birk}",
    year = "2018",
    doi = "10.1097/j.pain.0000000000001175",
    language = "English",
    volume = "159",
    pages = "1012--1024",
    journal = "Pain",
    issn = "0304-3959",
    publisher = "International Association for the Study of Pain",
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    Nasser, A, Møller, A, Hellmund, V, Thorborg, SS, Jespersgaard, C, Bjerrum, OJ, Dupont, E, Nachman, G, Lykkesfeldt, J, Jensen, T & Møller, LB 2018, 'Heterozygous mutations in GTP-cyclohydrolase-1 reduce BH4 biosynthesis but not pain sensitivity' Pain, bind 159, nr. 6, s. 1012-1024. https://doi.org/10.1097/j.pain.0000000000001175

    Heterozygous mutations in GTP-cyclohydrolase-1 reduce BH4 biosynthesis but not pain sensitivity. / Nasser, Arafat; Møller, Anette; Hellmund, Vibe; Thorborg, Sidsel Salling; Jespersgaard, Cathrine; Bjerrum, Ole Jannik; Dupont, Erik; Nachman, Gösta; Lykkesfeldt, Jens; Jensen, Troels; Møller, Lisbeth Birk.

    I: Pain, Bind 159, Nr. 6, 2018, s. 1012-1024.

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

    TY - JOUR

    T1 - Heterozygous mutations in GTP-cyclohydrolase-1 reduce BH4 biosynthesis but not pain sensitivity

    AU - Nasser, Arafat

    AU - Møller, Anette

    AU - Hellmund, Vibe

    AU - Thorborg, Sidsel Salling

    AU - Jespersgaard, Cathrine

    AU - Bjerrum, Ole Jannik

    AU - Dupont, Erik

    AU - Nachman, Gösta

    AU - Lykkesfeldt, Jens

    AU - Jensen, Troels

    AU - Møller, Lisbeth Birk

    PY - 2018

    Y1 - 2018

    N2 - 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.

    AB - 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.

    U2 - 10.1097/j.pain.0000000000001175

    DO - 10.1097/j.pain.0000000000001175

    M3 - Journal article

    VL - 159

    SP - 1012

    EP - 1024

    JO - Pain

    JF - Pain

    SN - 0304-3959

    IS - 6

    ER -

    Nasser A, Møller A, Hellmund V, Thorborg SS, Jespersgaard C, Bjerrum OJ et al. Heterozygous mutations in GTP-cyclohydrolase-1 reduce BH4 biosynthesis but not pain sensitivity. Pain. 2018;159(6):1012-1024. https://doi.org/10.1097/j.pain.0000000000001175