Multicenter Study

. 2022 Jan;37(1):137-147.

doi: 10.1002/mds.28804. Epub 2021 Oct 1.

Biallelic AOPEP Loss-of-Function Variants Cause Progressive Dystonia with Prominent Limb Involvement

Michael Zech^{1

2

3}, Kishore R Kumar^{4

5}, Sophie Reining⁶, Janine Reunert⁶, Michel Tchan^{7

8}, Lisa G Riley^{9

10}, Alexander P Drew⁵, Robert J Adam^{11

12}, Riccardo Berutti^{1

2

3}, Saskia Biskup¹³, Nicolas Derive¹⁴, Somayeh Bakhtiari^{15

16}, Sheng Chih Jin¹⁷, Michael C Kruer^{15

16}, Tanya Bardakjian¹⁸, Pedro Gonzalez-Alegre¹⁸, Ignacio J Keller Sarmiento¹⁹, Niccolo E Mencacci¹⁹, Steven J Lubbe¹⁹, Manju A Kurian^{20

21}, Fabienne Clot^{14

22}, Aurélie Méneret²³, Jean-Madeleine de Sainte Agathe^{14

24}, Victor S C Fung^{25

26}, Marie Vidailhet²³, Matthias Baumann²⁷, Thorsten Marquardt⁶, Juliane Winkelmann^{1

2

3

28

29}, Sylvia Boesch³⁰

Affiliations

¹ Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.
² Technical University of Munich, Munich, Germany.
³ School of Medicine, Technical University of Munich, Institute of Human Genetics, Munich, Germany.
⁴ Molecular Medicine Laboratory and Neurology Department, Concord Clinical School, Concord Repatriation General Hospital, The University of Sydney, Sydney, New South Wales, Australia.
⁵ Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
⁶ Department of General Paediatrics, University of Münster, Münster, Germany.
⁷ Department of Genetic Medicine, Westmead Hospital, Westmead, New South Wales, Australia.
⁸ Sydney Medical School, University of Sydney, Camperdown, New South Wales, Australia.
⁹ Discipline of Child & Adolescent Health, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
¹⁰ Rare Diseases Functional Genomics, Kids Research, The Children's Hospital at Westmead and The Children's Medical Research Institute, Sydney, New South Wales, Australia.
¹¹ Department of Neurology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
¹² Centre for Clinical Research, The University of Queensland, Brisbane, Queensland, Australia.
¹³ CeGaT GmbH und Praxis für Humangenetik Tübingen, Tübingen, Germany.
¹⁴ Laboratoire de Biologie Médicale Multi-Sites SeqOIA, Paris, France.
¹⁵ Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, Arizona, USA.
¹⁶ Departments of Child Health, Neurology, and Cellular & Molecular Medicine, and Program in Genetics, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, USA.
¹⁷ Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.
¹⁸ Department of Neurology, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹⁹ Ken and Ruth Davee Department of Neurology, and Simpson Querrey Center for Neurogenetics, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.
²⁰ Department of Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.
²¹ Department of Neurology, Great Ormond Street Hospital, London, United Kingdom.
²² AP-HP Sorbonne Université, Département de Génétique, UF de Neurogénétique Moléculaire et Cellulaire, Hôpital Pitié-Salpêtrière, Paris, France.
²³ Sorbonne Université, Paris Brain Institute-ICM, Inserm, CNRS, Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, DMU Neurosciences, Paris, France.
²⁴ AP-HP Sorbonne Université, Laboratoire de Médecine Génomique, Hôpital Pitié-Salpêtrière, Paris, France.
²⁵ Movement Disorders Unit, Neurology Department, Westmead Hospital, Westmead, New South Wales, Australia.
²⁶ Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
²⁷ Department of Pediatrics, Medical University of Innsbruck, Innsbruck, Austria.
²⁸ Lehrstuhl für Neurogenetik, Technische Universität München, Munich, Germany.
²⁹ Munich Cluster for Systems Neurology, SyNergy, Munich, Germany.
³⁰ Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.

PMID: 34596301
DOI: 10.1002/mds.28804

Multicenter Study

Biallelic AOPEP Loss-of-Function Variants Cause Progressive Dystonia with Prominent Limb Involvement

Michael Zech et al. Mov Disord. 2022 Jan.

. 2022 Jan;37(1):137-147.

doi: 10.1002/mds.28804. Epub 2021 Oct 1.

Authors

Affiliations

¹ Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.
² Technical University of Munich, Munich, Germany.
³ School of Medicine, Technical University of Munich, Institute of Human Genetics, Munich, Germany.
⁴ Molecular Medicine Laboratory and Neurology Department, Concord Clinical School, Concord Repatriation General Hospital, The University of Sydney, Sydney, New South Wales, Australia.
⁵ Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
⁶ Department of General Paediatrics, University of Münster, Münster, Germany.
⁷ Department of Genetic Medicine, Westmead Hospital, Westmead, New South Wales, Australia.
⁸ Sydney Medical School, University of Sydney, Camperdown, New South Wales, Australia.
⁹ Discipline of Child & Adolescent Health, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
¹⁰ Rare Diseases Functional Genomics, Kids Research, The Children's Hospital at Westmead and The Children's Medical Research Institute, Sydney, New South Wales, Australia.
¹¹ Department of Neurology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
¹² Centre for Clinical Research, The University of Queensland, Brisbane, Queensland, Australia.
¹³ CeGaT GmbH und Praxis für Humangenetik Tübingen, Tübingen, Germany.
¹⁴ Laboratoire de Biologie Médicale Multi-Sites SeqOIA, Paris, France.
¹⁵ Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, Arizona, USA.
¹⁶ Departments of Child Health, Neurology, and Cellular & Molecular Medicine, and Program in Genetics, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, USA.
¹⁷ Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.
¹⁸ Department of Neurology, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹⁹ Ken and Ruth Davee Department of Neurology, and Simpson Querrey Center for Neurogenetics, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.
²⁰ Department of Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.
²¹ Department of Neurology, Great Ormond Street Hospital, London, United Kingdom.
²² AP-HP Sorbonne Université, Département de Génétique, UF de Neurogénétique Moléculaire et Cellulaire, Hôpital Pitié-Salpêtrière, Paris, France.
²³ Sorbonne Université, Paris Brain Institute-ICM, Inserm, CNRS, Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, DMU Neurosciences, Paris, France.
²⁴ AP-HP Sorbonne Université, Laboratoire de Médecine Génomique, Hôpital Pitié-Salpêtrière, Paris, France.
²⁵ Movement Disorders Unit, Neurology Department, Westmead Hospital, Westmead, New South Wales, Australia.
²⁶ Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
²⁷ Department of Pediatrics, Medical University of Innsbruck, Innsbruck, Austria.
²⁸ Lehrstuhl für Neurogenetik, Technische Universität München, Munich, Germany.
²⁹ Munich Cluster for Systems Neurology, SyNergy, Munich, Germany.
³⁰ Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.

PMID: 34596301
DOI: 10.1002/mds.28804

Abstract

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.

Keywords: AOPEP; genomic analysis; loss-of-function variants; monogenic dystonia; rare disease.

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Comment in

Expanded Genetic Spectrum and Variable Disease Onset in AOPEP-Associated Dystonia.
Menden B, Gutschalk A, Wunderlich G, Haack TB. Menden B, et al. Mov Disord. 2022 May;37(5):1113-1115. doi: 10.1002/mds.29021. Mov Disord. 2022. PMID: 35587627 No abstract available.

References

1. Albanese A, Bhatia K, Bressman SB, et al. Phenomenology and classification of dystonia: a consensus update. Mov Disord 2013;28(7):863-873.
1. Balint B, Mencacci NE, Valente EM, et al. Dystonia. Nat Rev Dis Primers 2018;4(1):25.
1. Keller Sarmiento IJ, Mencacci NE. Genetic dystonias: update on classification and new genetic discoveries. Curr Neurol Neurosci Rep 2021;21(3):8.
1. Kumar KR, Davis RL, Tchan MC, et al. Whole genome sequencing for the genetic diagnosis of heterogenous dystonia phenotypes. Parkinsonism Relat Disord 2019;69:111-118.
1. Zech M, Jech R, Boesch S, et al. Monogenic variants in dystonia: an exome-wide sequencing study. Lancet Neurol 2020;19(11):908-918.

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Biallelic AOPEP Loss-of-Function Variants Cause Progressive Dystonia with Prominent Limb Involvement

Affiliations

Biallelic AOPEP Loss-of-Function Variants Cause Progressive Dystonia with Prominent Limb Involvement

Authors

Affiliations

Abstract

Comment in

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

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