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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 137-147 |
| Number of pages | 11 |
| Journal | Movement Disorders |
| Volume | 37 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2022 |
Funding
Dr. K.R. Kumar received funding from the Paul Ainsworth Family Foundation and honorarium from Seqirus. Dr. A.P. Drew received funding from the Kinghorn Foundation and Cure Parkinson's Trust (UK). Dr. S. Bakhtiari received research support (grant) from the Cerebral Palsy Alliance Research Foundation (Career Development Award; CDG01318). Dr. J.‐M. de Sainte Agathe received financial support from the Laboratoire de Medicine Genomique Sorbonne University (employment). Dr. M. Baumann has a relationship to advisory boards of Biogen, Novartis, and Roche. Dr. S. Boesch has a relationship to advisory boards of Stada, AbbVie, and Ipsen; has received honoraria from Ipsen, Allergan, Merz, AbbVie, and Reata; and has received research support (grants) from EFACTS, FP7 Health, and E‐Rare‐3. All other authors declare no conflict of interest. This study was funded by in‐house institutional funding from Technische Universität München (Munich, Germany), Helmholtz Zentrum München (Munich, Germany), and Medizinische Universität Innsbruck (Innsbruck, Austria). M.Z. and J.W. received research support from the German Research Foundation (DFG 458949627, ZE 1213/2‐1, and WI 1820/14‐1). S. Boesch is a member of the European Reference Network for Rare Neurological Diseases (Project ID No. 739510). K.R.K. received funding from the Paul Ainsworth Family Foundation. We thank the families who participated in this study. We thank Dora Steel, BMBCh (Great Ormond Street Hospital, London, UK) for querying genomic data for variants. Biospecimens used in the analyses presented in this article were obtained from the Northwestern University Movement Disorders Center (MDC) Biorepository. As such, the investigators within MDC Biorepository contributed to the design and implementation of the MDC Biorepository and/or provided data and collected biospecimens but did not participate in the analysis or writing of this report. MDC Biorepository investigators include: Tanya Simuni, MD; Dimitri Krainc, MD, PhD; Opal Puneet, MD, PhD; Cindy Zadikoff, MD; Onur Melen, MD; Danny Bega, MD; Roneil G. Malkani, MD; Steven Lubbe, PhD; Niccolo E. Mencacci, MD, PhD; Christina Zelano, PhD; Joanna Blackburn, MD; Firas Wehbe, MD, PhD; Lisa Kinsley, MS, CGC; and Tina Ward, MS. A gift from the Malkin family generously supported the work of the MDC Biorepository. We gratefully thank Laurène Tissier, MLT, for her generous contribution with Sanger sequencing of individuals from family IV. Open Access funding enabled and organized by Projekt DEAL. AOPEP This study was funded by in-house institutional funding from Technische Universit?t M?nchen (Munich, Germany), Helmholtz Zentrum M?nchen (Munich, Germany), and Medizinische Universit?t Innsbruck (Innsbruck, Austria). M.Z. and J.W. received research support from the German Research Foundation (DFG 458949627, ZE 1213/2-1, and WI 1820/14-1). S. Boesch is a member of the European Reference Network for Rare Neurological Diseases (Project ID No. 739510). K.R.K. received funding from the Paul Ainsworth Family Foundation. We thank the families who participated in this study. We thank Dora Steel, BMBCh (Great Ormond Street Hospital, London, UK) for querying genomic data for AOPEP variants. Biospecimens used in the analyses presented in this article were obtained from the Northwestern University Movement Disorders Center (MDC) Biorepository. As such, the investigators within MDC Biorepository contributed to the design and implementation of the MDC Biorepository and/or provided data and collected biospecimens but did not participate in the analysis or writing of this report. MDC Biorepository investigators include: Tanya Simuni, MD; Dimitri Krainc, MD, PhD; Opal Puneet, MD, PhD; Cindy Zadikoff, MD; Onur Melen, MD; Danny Bega, MD; Roneil G. Malkani, MD; Steven Lubbe, PhD; Niccolo E. Mencacci, MD, PhD; Christina Zelano, PhD; Joanna Blackburn, MD; Firas Wehbe, MD, PhD; Lisa Kinsley, MS, CGC; and Tina Ward, MS. A gift from the Malkin family generously supported the work of the MDC Biorepository. We gratefully thank Laur?ne Tissier, MLT, for her generous contribution with Sanger sequencing of individuals from family IV. Open Access funding enabled and organized by Projekt DEAL.
ASJC Scopus subject areas
- Neurology
- Clinical Neurology
