De Novo Mutation in TMEM151A and Paroxysmal Kinesigenic Dyskinesia

Movement DisordersVolume 37, Issue 5 p. 1115-1117 Letters: Published ArticlesOpen Access De Novo Mutation in TMEM151A and Paroxysmal Kinesigenic Dyskinesia Thomas Wirth MD, MS, Corresponding Author Thomas Wirth MD, MS thomas.wirth@etu.unistra.fr orcid.org/0000-0002-4427-5765 Service de Neurologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé Et de la Recherche Médicale-U964/Centre National de la Recherche Scientifique-UMR7104/Université de Strasbourg, Illkirch-Graffenstaden, France Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France These authors contributed equally and should be considered as co-first authors. Correspondence to: Dr. Thomas Wirth, Neurology Department, Strasbourg University Hospital, 67098 Strasbourg, France. E-mail: thomas.wirth@etu.unistra.frSearch for more papers by this authorAurélie Méneret MD, PhD, Aurélie Méneret MD, PhD orcid.org/0000-0002-7623-1142 Département de neurologie, Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris, France Sorbonne Université, Institut du Cerveau, Institut National de la Santé Et de la Recherche Médicale-U1127/Centre National de la Recherche Scientifique-UMR7225, Salpêtrière Hospital, AP-HP, Paris, France These authors contributed equally and should be considered as co-first authors.Search for more papers by this authorNathalie Drouot PhD, Nathalie Drouot PhD Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé Et de la Recherche Médicale-U964/Centre National de la Recherche Scientifique-UMR7104/Université de Strasbourg, Illkirch-Graffenstaden, FranceSearch for more papers by this authorGabrielle Rudolf PhD, Gabrielle Rudolf PhD Service de Neurologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé Et de la Recherche Médicale-U964/Centre National de la Recherche Scientifique-UMR7104/Université de Strasbourg, Illkirch-Graffenstaden, France Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, FranceSearch for more papers by this authorOuhaid Lagha Boukbiza MD, Ouhaid Lagha Boukbiza MD Service de Neurologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, FranceSearch for more papers by this authorJamel Chelly MD, PhD, Jamel Chelly MD, PhD Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé Et de la Recherche Médicale-U964/Centre National de la Recherche Scientifique-UMR7104/Université de Strasbourg, Illkirch-Graffenstaden, France Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, FranceSearch for more papers by this authorChristine Tranchant MD, PhD, Christine Tranchant MD, PhD Service de Neurologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé Et de la Recherche Médicale-U964/Centre National de la Recherche Scientifique-UMR7104/Université de Strasbourg, Illkirch-Graffenstaden, France Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, FranceSearch for more papers by this authorAmélie Piton PhD, Amélie Piton PhD Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé Et de la Recherche Médicale-U964/Centre National de la Recherche Scientifique-UMR7104/Université de Strasbourg, Illkirch-Graffenstaden, France Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, FranceSearch for more papers by this authorEmmanuel Roze MD, PhD, Emmanuel Roze MD, PhD Département de neurologie, Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris, France Sorbonne Université, Institut du Cerveau, Institut National de la Santé Et de la Recherche Médicale-U1127/Centre National de la Recherche Scientifique-UMR7225, Salpêtrière Hospital, AP-HP, Paris, France These authors contributed equally and should be considered as co-last authors.Search for more papers by this authorMathieu Anheim MD, PhD, Mathieu Anheim MD, PhD Service de Neurologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé Et de la Recherche Médicale-U964/Centre National de la Recherche Scientifique-UMR7104/Université de Strasbourg, Illkirch-Graffenstaden, France Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France These authors contributed equally and should be considered as co-last authors.Search for more papers by this author Thomas Wirth MD, MS, Corresponding Author Thomas Wirth MD, MS thomas.wirth@etu.unistra.fr orcid.org/0000-0002-4427-5765 Service de Neurologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé Et de la Recherche Médicale-U964/Centre National de la Recherche Scientifique-UMR7104/Université de Strasbourg, Illkirch-Graffenstaden, France Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France These authors contributed equally and should be considered as co-first authors. Correspondence to: Dr. Thomas Wirth, Neurology Department, Strasbourg University Hospital, 67098 Strasbourg, France. E-mail: thomas.wirth@etu.unistra.frSearch for more papers by this authorAurélie Méneret MD, PhD, Aurélie Méneret MD, PhD orcid.org/0000-0002-7623-1142 Département de neurologie, Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris, France Sorbonne Université, Institut du Cerveau, Institut National de la Santé Et de la Recherche Médicale-U1127/Centre National de la Recherche Scientifique-UMR7225, Salpêtrière Hospital, AP-HP, Paris, France These authors contributed equally and should be considered as co-first authors.Search for more papers by this authorNathalie Drouot PhD, Nathalie Drouot PhD Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé Et de la Recherche Médicale-U964/Centre National de la Recherche Scientifique-UMR7104/Université de Strasbourg, Illkirch-Graffenstaden, FranceSearch for more papers by this authorGabrielle Rudolf PhD, Gabrielle Rudolf PhD Service de Neurologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé Et de la Recherche Médicale-U964/Centre National de la Recherche Scientifique-UMR7104/Université de Strasbourg, Illkirch-Graffenstaden, France Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, FranceSearch for more papers by this authorOuhaid Lagha Boukbiza MD, Ouhaid Lagha Boukbiza MD Service de Neurologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, FranceSearch for more papers by this authorJamel Chelly MD, PhD, Jamel Chelly MD, PhD Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé Et de la Recherche Médicale-U964/Centre National de la Recherche Scientifique-UMR7104/Université de Strasbourg, Illkirch-Graffenstaden, France Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, FranceSearch for more papers by this authorChristine Tranchant MD, PhD, Christine Tranchant MD, PhD Service de Neurologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé Et de la Recherche Médicale-U964/Centre National de la Recherche Scientifique-UMR7104/Université de Strasbourg, Illkirch-Graffenstaden, France Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, FranceSearch for more papers by this authorAmélie Piton PhD, Amélie Piton PhD Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé Et de la Recherche Médicale-U964/Centre National de la Recherche Scientifique-UMR7104/Université de Strasbourg, Illkirch-Graffenstaden, France Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, FranceSearch for more papers by this authorEmmanuel Roze MD, PhD, Emmanuel Roze MD, PhD Département de neurologie, Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris, France Sorbonne Université, Institut du Cerveau, Institut National de la Santé Et de la Recherche Médicale-U1127/Centre National de la Recherche Scientifique-UMR7225, Salpêtrière Hospital, AP-HP, Paris, France These authors contributed equally and should be considered as co-last authors.Search for more papers by this authorMathieu Anheim MD, PhD, Mathieu Anheim MD, PhD Service de Neurologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé Et de la Recherche Médicale-U964/Centre National de la Recherche Scientifique-UMR7104/Université de Strasbourg, Illkirch-Graffenstaden, France Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France These authors contributed equally and should be considered as co-last authors.Search for more papers by this author First published: 19 May 2022 https://doi.org/10.1002/mds.29023 Relevant conflicts of interest/financial disclosures:: Nothing to report. Funding agencies:: Thomas Wirth received a research grant from the Revue Neurologique for this work. This study was funded by a grant from the Fondation Maladies Rares. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat We read with great interest the article by Tian and colleagues.1 Heterozygous mutations in TMEM151A, encoding transmembrane protein 151 A, a protein of undetermined function, have been very recently associated with paroxysmal kinesigenic dyskinesia (PKD) in the Chinese population.1-4 TMEM151A is highly expressed in the brain, including the cerebral cortex and the thalamus and is highly conserved among species. To definitively confirm the association between TMEM151A and PKD, other mutations in the same gene should be identified in independent cohorts from different populations. We applied whole exome sequencing (WES) on 23 French patients with sporadic PKD who tested negative for PRRT2 (proline-rich transmembrane protein 2) mutations as well as their asymptomatic parents. PKD diagnosis was made by movement disorders specialists according to the consensus clinical criteria.5 WES, bioinformatic analysis, and variant prioritization were performed as previously described.6 Variants were classified according to the American College of Human Genetics and Genomics (ACMG) criteria.7 All patients gave written informed consent before genetic testing, and a local ethics committee approved the study. We identified a de novo missense variant (c.166G > C [p.Gly56Arg]) in TMEM151A in a single patient (Fig. 1) through trio-based exome sequencing. This variant, absent from public databases including Exac, 1000G, and GnomAD, led to a substitution in the second transmembrane domain of the protein near previously reported pathogenic variants, such as c.140 T > C [p.Leu47Pro] or c.133 T > G [p.Cys45Arg]. It was predicted to be damaging by Polyphen, with a Combined Annotation Dependent Depletion (CADD) score above 20. The phenotype was consistent with previous reports of TMEM151A-related PKD. The patient had no history of infantile seizures and presented with brief attacks of dystonia triggered by voluntary movements, surprise, or stressful events beginning after age 16. Before medication initiation, the patient experienced between 10 and 20 attacks a day, usually lasting a few dozens of seconds. Attacks could be focal or generalized, affecting speech or involving the face or upper and lower limbs subsequently or simultaneously. The attacks totally ceased after the initiation of low doses of lamotrigine (50 mg/d). This variant was subsequently classified as likely pathogenic (class IV) according to the ACMG criteria (PS2 + PM1 + PM2 + PP2 + PP4).7 No other de novo class IV or V variant was identified in this cohort. The TMEM151A mutation was identified in one of 23 patients of our PRRT2-negative PKD cohort, which is in accordance with the frequency of 4.8% found by Tian et al.1 FIG 1Open in figure viewerPowerPoint (A) Pedigree of the family. WT: Wild Type (B) Visualization of the (c.166G > C [p.Gly56Arg]) variant (between red lines) in the patient in the TMEM151A (Transmembrane protein 151 A) sequence through the Integrated Genome Viewer. The replacement of the reference G by a C (blue) is present on half of the patient's read, meaning heterozygosity. (C) Sanger sequencing of the (c.166G > C [p.Gly56Arg]) variant (between red lines). The variant is present in a heterozygous state in the patient but absent in the two asymptomatic parents, compatible with a de novo occurrence. [Color figure can be viewed at wileyonlinelibrary.com] We report on a de novo mutation in TMEM151A in a patient with PKD. Our findings confirm TMEM151A variants as a genetic cause of PKD and suggest that de novo mutations in this gene are infrequently responsible for sporadic PKD cases.4 Further works are warranted to refine the phenotype/genotype correlations among TMEM151A-related disorders. Whether TMEM151A is a transmembrane protein involved in synaptic function and whether TMEM151A-related PKD is underpinned by its loss of function also remain to be elucidated. Data Availability Statement Anonymized data pertaining to the research presented will be made available upon reasonable request from external investigators. Author Roles (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing First Draft, B. Review and Critique. T.W.: 1A, 1C, 2C, 3A A.M.: 1A, 1C, 2C, 3B N.D.: 1C, 2C G.R.: 1C, 2C O.L.B.: 1C J.C.: 1A, 1C, 3B C.T.: 1A, 1C, 3B A.P.: 1A, 1C, 3B E.R.: 1A, 1B, 1C, 3B M.A.: 1A, 1B, 1C, 2C, 3B Financial Disclosures Thomas Wirth received grants from the Revue Neurologique, the Fondation Planiol, and the Association des Personnes Concernées par le Tremblement Essentiel (APTES) organizations and travel funding from LVL Medical. Aurélie Méneret received speaker honoraria from Abbvie. Emmanuel Roze received honorarium from Orkyn, Aguettant, and Elivie for speeches and for participating in the advisory board of Allergan and received research support from Merz-Pharma, Orkyn, Aguettant, Elivie, Ipsen, Allergan, Everpharma, Fondation Desmarest, Association des Malades Atteints de Dystonie (AMADYS), ADCY5.org, Agence Nationale de la Recherche, Societé Française de Médecine Esthétique, and the Dystonia Medical Research Foundation. The other authors declare no competing interest. Open Research Data Availability Statement Anonymized data pertaining to the research presented will be made available upon reasonable request from external investigators. References 1Tian W-T, Zhan F-X, Liu Z-H, Liu Z, Liu Q, Guo X-N, et al. TMEM151A variants cause paroxysmal Kinesigenic dyskinesia: a large-sample study. Mov Disord 2021; 37: 545– 552. Wiley Online LibraryPubMedWeb of Science®Google Scholar 2Li H-F, Chen Y-L, Zhuang L, Chen D-F, Ke H-Z, Luo W-J, et al. TMEM151A variants cause paroxysmal kinesigenic dyskinesia. Cell Discov 2021; 7: 83CrossrefCASPubMedWeb of Science®Google Scholar 3Li Y-L, Lv W-Q, Zeng Y-H, Chen Y-K, Wang X-L, Yang K, et al. Exome-wide analyses in paroxysmal Kinesigenic dyskinesia confirm TMEM151A as a novel causative gene. Mov Disord 2021; 37: 641– 643. Wiley Online LibraryPubMedWeb of Science®Google Scholar 4Chen Y-L, Chen D-F, Li H-F, Wu Z-Y. Features differ between paroxysmal Kinesigenic dyskinesia patients with PRRT2 and TMEM151A variants. Mov Disord 2022; 37(3): 608– 613. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 5Méneret A, Grabli D, Depienne C, Gaudebout C, Picard F, Dürr A, et al. PRRT2 mutations: a major cause of paroxysmal kinesigenic dyskinesia in the European population. Neurology 2012; 79(2): 170– 174. CrossrefCASPubMedWeb of Science®Google Scholar 6Wirth T, Tranchant C, Drouot N, Keren B, Mignot C, Cif L, et al. Increased diagnostic yield in complex dystonia through exome sequencing. Parkinsonism Relat Disord 2020; 74: 50– 56. CrossrefPubMedWeb of Science®Google Scholar 7Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17(5): 405– 424. CrossrefPubMedWeb of Science®Google Scholar Volume37, Issue5May 2022Pages 1115-1117 FiguresReferencesRelatedInformation