Zech M1 2 3, Kumar KR4 5, Reining S6, Reunert J6, Tchan M7 8, Riley LG9 10, Drew AP5, Adam RJ11 12, Berutti R1 2 3, Biskup S13, Derive N14, Bakhtiari S15 16, Jin SC17, Kruer MC15 16, Bardakjian T18, Gonzalez-Alegre P18, Keller Sarmiento IJ19, Mencacci NE19, Lubbe SJ19, Kurian MA20 21, Clot F14 22, Méneret A23, de Sainte Agathe JM14 24, Fung VSC25 26, Vidailhet M23, Baumann M27, Marquardt T6, Winkelmann J1 2 3 28 29, Boesch S30
Background: Monogenic causes of isolated dystonia are heterogeneous. Assembling cohorts of affected individuals sufficiently large to establish new gene-disease relationships can be challenging.
Objective: We sought to expand the catalogue of monogenic etiologies for isolated dystonia.
Methods: After the discovery of a candidate variant in a multicenter exome-sequenced cohort of affected individuals with dystonia, we queried online platforms and genomic data repositories worldwide to identify subjects with matching genotypic profiles.
Results: Seven different biallelic loss-of-function variants in AOPEP were detected in five probands from four unrelated families with strongly overlapping phenotypes. In one proband, we observed a homozygous nonsense variant (c.1477C>T [p.Arg493*]). A second proband harbored compound heterozygous nonsense variants (c.763C>T [p.Arg255*]; c.777G>A [p.Trp259*]), whereas a third proband possessed a frameshift variant (c.696_697delAG [p.Ala234Serfs*5]) in trans with a splice-disrupting alteration (c.2041-1G>A). Two probands (siblings) from a fourth family shared compound heterozygous frameshift alleles (c.1215delT [p.Val406Cysfs*14]; c.1744delA [p.Met582Cysfs*6]). All variants were rare and expected to result in truncated proteins devoid of functionally important amino acid sequence. AOPEP, widely expressed in developing and adult human brain, encodes a zinc-dependent aminopeptidase, a member of a class of proteolytic enzymes implicated in synaptogenesis and neural maintenance. The probands presented with disabling progressive dystonia predominantly affecting upper and lower extremities, with variable involvement of craniocervical muscles. Dystonia was unaccompanied by any additional symptoms in three families, whereas the fourth family presented co-occurring late-onset parkinsonism.
Conclusions: Our findings suggest a likely causative role of predicted inactivating biallelic AOPEP variants in cases of autosomal recessive dystonia. Additional studies are warranted to understand the pathophysiology associated with loss-of-function variation in AOPEP. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
- Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.
- Technical University of Munich, Munich, Germany.
- School of Medicine, Technical University of Munich, Institute of Human Genetics, Munich, Germany.
- Molecular Medicine Laboratory and Neurology Department, Concord Clinical School, Concord Repatriation General Hospital, The University of Sydney, Sydney, New South Wales, Australia.
- Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
- Department of General Paediatrics, University of Münster, Münster, Germany.
- Department of Genetic Medicine, Westmead Hospital, Westmead, New South Wales, Australia.
- Sydney Medical School, University of Sydney, Camperdown, New South Wales, Australia.
- Discipline of Child & Adolescent Health, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
- Rare Diseases Functional Genomics, Kids Research, The Children’s Hospital at Westmead and The Children’s Medical Research Institute, Sydney, New South Wales, Australia.
- Department of Neurology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia.
- Centre for Clinical Research, The University of Queensland, Brisbane, Queensland, Australia.
- CeGaT GmbH und Praxis für Humangenetik Tübingen, Tübingen, Germany.
- Laboratoire de Biologie Médicale Multi-Sites SeqOIA, Paris, France.
- Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, Arizona, USA.
- Departments of Child Health, Neurology, and Cellular & Molecular Medicine, and Program in Genetics, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, USA.
- Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.
- Department of Neurology, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, USA.
- Ken and Ruth Davee Department of Neurology, and Simpson Querrey Center for Neurogenetics, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.
- Department of Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.
- Department of Neurology, Great Ormond Street Hospital, London, United Kingdom.
- AP-HP Sorbonne Université, Département de Génétique, UF de Neurogénétique Moléculaire et Cellulaire, Hôpital Pitié-Salpêtrière, Paris, France.
- Sorbonne Université, Paris Brain Institute-ICM, Inserm, CNRS, Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, DMU Neurosciences, Paris, France.
- AP-HP Sorbonne Université, Laboratoire de Médecine Génomique, Hôpital Pitié-Salpêtrière, Paris, France.
- Movement Disorders Unit, Neurology Department, Westmead Hospital, Westmead, New South Wales, Australia.
- Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia..
- Department of Pediatrics, Medical University of Innsbruck, Innsbruck, Austria.
- Lehrstuhl für Neurogenetik, Technische Universität München, Munich, Germany.
- Munich Cluster for Systems Neurology, SyNergy, Munich, Germany.
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.