{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T22:31:50Z","timestamp":1788474710074,"version":"build-2803163510"},"reference-count":35,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,10,1]],"date-time":"2021-10-01T00:00:00Z","timestamp":1633046400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["movementdisorders.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Movement Disorders"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Monogenic causes of isolated dystonia are heterogeneous. Assembling cohorts of affected individuals sufficiently large to establish new gene\u2013disease relationships can be challenging.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>We sought to expand the catalogue of monogenic etiologies for isolated dystonia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>After the discovery of a candidate variant in a multicenter exome\u2010sequenced cohort of affected individuals with dystonia, we queried online platforms and genomic data repositories worldwide to identify subjects with matching genotypic profiles.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Seven different biallelic loss\u2010of\u2010function variants in <jats:italic>AOPEP<\/jats:italic> were detected in five probands from four unrelated families with strongly overlapping phenotypes. In one proband, we observed a homozygous nonsense variant (c.1477C&gt;T [p.Arg493*]). A second proband harbored compound heterozygous nonsense variants (c.763C&gt;T [p.Arg255*]; c.777G&gt;A [p.Trp259*]), whereas a third proband possessed a frameshift variant (c.696_697delAG [p.Ala234Serfs*5]) in <jats:italic>trans<\/jats:italic> with a splice\u2010disrupting alteration (c.2041\u20101G&gt;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. <jats:italic>AOPEP<\/jats:italic>, widely expressed in developing and adult human brain, encodes a zinc\u2010dependent 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\u2010occurring late\u2010onset parkinsonism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings suggest a likely causative role of predicted inactivating biallelic <jats:italic>AOPEP<\/jats:italic> variants in cases of autosomal recessive dystonia. Additional studies are warranted to understand the pathophysiology associated with loss\u2010of\u2010function variation in <jats:italic>AOPEP<\/jats:italic>. \u00a9 2021 The Authors. <jats:italic>Movement Disorders<\/jats:italic> published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society<\/jats:p><\/jats:sec>","DOI":"10.1002\/mds.28804","type":"journal-article","created":{"date-parts":[[2021,10,1]],"date-time":"2021-10-01T17:04:20Z","timestamp":1633107860000},"page":"137-147","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Biallelic <scp><i>AOPEP<\/i><\/scp> Loss\u2010of\u2010Function Variants Cause Progressive Dystonia with Prominent Limb Involvement"],"prefix":"10.1002","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8112-9153","authenticated-orcid":false,"given":"Michael","family":"Zech","sequence":"first","affiliation":[{"name":"Institute of 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