Association of Rare Genetic Variants in Opioid Receptors with Tourette Syndrome

Tremor and Other Hyperkinetic Movements

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Christel Depienne¹  Sorana Ciura¹  Oriane Trouillard¹  Delphine Bouteiller¹  Elsa Leitão²  Caroline Nava¹  Boris Keren³  Yannick Marie¹  Justine Guegan¹  Sylvie Forlani¹  Alexis Brice¹  Mathieu Anheim⁴  Yves Agid¹  Paul Krack⁵  Philippe Damier⁷  François Viallet⁸  Jean-Luc Houeto⁹  Franck Durif^1,10  Marie Vidailhet¹  Yulia Worbe¹  Emmanuel Roze¹  Edor Kabashi¹  Andreas Hartmann¹ 

[1] Faculté de Médecine de Sorbonne Université, Institut du Cerveau et de la Moelle épinière;Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen;Assistance Publique Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, Département de Génétique;Service de neurologie, CHU de Strasbourg, Hôpital de Hautepierre;Service de Neurologie, CHU de Grenoble, Avenue Maquis du Grésivaudan;Center for Movement Disorders, University of Bern;Service de Neurologie, CHU de Nantes;Service de Neurologie, CRHU d’Aix-en-Provence;Service de Neurologie, CHU de Poitiers;Service de Neurologie, CHU de Clermont-Ferrand, CHU de Clermont-Ferrand, Hôpital Gabriel Montpied;Assistance Publique Hôpitaux de Paris (APHP), Hôpital Pitié-Salpêtrière, Département de Neurologie;Centre de Référence National Maladie Rare ‘Syndrome Gilles de la Tourette’

关键词: Tourette syndrome;    gene;    variant;    susceptibility factor;    opioid receptor;    zebrafish;    OPRK1;   

DOI  :  10.5334/tohm.464

学科分类：社会科学、人文和艺术（综合）

来源: Ubiquity Press

【 摘 要 】

Background: Genes involved in Tourette syndrome (TS) remain largely unknown. We aimed to identify genetic factors contributing to TS in a French cohort of 120 individuals using a combination of hypothesis-driven and exome-sequencing approaches. Methods: We first sequenced exons of SLITRK1-6 and HDC in the TS cohort and subsequently sequenced the exome of 12 individuals harboring rare variants in these genes to find additional rare variants contributing to the disorder under the hypothesis of oligogenic inheritance. We further screened three candidate genes ( OPRK1, PCDH10 , and NTSR2 ) preferentially expressed in the basal ganglia, and three additional genes involved in neurotensin and opioid signaling ( OPRM1 , NTS , and NTSR1 ), and compared variant frequencies in TS patients and 788 matched control individuals. We also investigated the impact of altering the expression of Oprk1 in zebrafish. Results: Thirteen ultrarare missense variants of SLITRK1-6 and HDC were identified in 12 patients. Exome sequencing in these patients revealed rare possibly deleterious variants in 3,041 genes, 54 of which were preferentially expressed in the basal ganglia. Comparison of variant frequencies altering selected candidate genes in TS and control individuals revealed an excess of potentially disrupting variants in OPRK1 , encoding the opioid kappa receptor, in TS patients. Accordingly, we show that downregulation of the Oprk1 orthologue in zebrafish induces a hyperkinetic phenotype in early development. Discussion: These results support a heterogeneous and complex genetic etiology of TS, possibly involving rare variants altering the opioid pathway in some individuals, which could represent a novel therapeutic target in this disorder.

【 授权许可】

CC BY