{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T11:19:39Z","timestamp":1780571979340,"version":"3.54.1"},"reference-count":56,"publisher":"BMJ","issue":"6","content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2025,3,17]]},"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:p>Gene discovery efforts have contributed to a better understanding of the molecular causes of dystonia, but knowledge of the individual monogenic forms remains limited. This review seeks to summarise all available data on the recently identified autosomal recessive subtype of dystonia caused by variants in <jats:italic>AOPEP<\/jats:italic>, focusing on the geographical origins of affected families, mutational spectrum, phenotypic expressions and pathophysiology. <jats:italic>AOPEP<\/jats:italic>-related dystonia, documented as Zech-Boesch syndrome in the Online Mendelian Inheritance in Man database, has been diagnosed in cohorts around the globe including under-represented populations with increased rates of consanguinity. Predictably leading to loss of protein function, the majority (74%) of disease-associated <jats:italic>AOPEP<\/jats:italic> alleles are protein-truncating variants comprising homozygous and compound heterozygous stop-gain, frameshift and splice-site changes. The dystonic disorder shows onset from childhood to the fourth decade and generalises in a significant proportion of cases (60%). Variable expressivity and age-related penetrance are likely to play a role in manifestation of the condition, consistent with occasional occurrence of <jats:italic>AOPEP<\/jats:italic> homozygous pathogenic variants in subjects without a diagnosis of dystonia. <jats:italic>AOPEP<\/jats:italic> encodes aminopeptidase O, a proteolytic processing enzyme that is preferentially expressed in glia and potentially linked to endosomal-lysosomal pathways. <jats:italic>AOPEP<\/jats:italic>-related autosomal recessive Zech-Boesch syndrome is of worldwide relevance for the diagnosis of genetic dystonia. Future research focusing on <jats:italic>AOPEP<\/jats:italic>\u02cbs role in cellular protein metabolism may provide new insights into dystonia pathogenesis and yet-unidentified therapeutic targets.<\/jats:p>","DOI":"10.1136\/jmg-2025-110656","type":"journal-article","created":{"date-parts":[[2025,3,27]],"date-time":"2025-03-27T15:36:36Z","timestamp":1743089796000},"page":"388-395","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":6,"title":["<i>AOPEP<\/i>-related autosomal recessive dystonia: update on Zech-Boesch syndrome"],"prefix":"10.1136","volume":"62","author":[{"given":"Sylvia","family":"Boesch","sequence":"first","affiliation":[{"name":"Department of Neurology, Medical University of Innsbruck, Innsbruk, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8112-9153","authenticated-orcid":false,"given":"Michael","family":"Zech","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, School of Medicine and Health, Technical University of Munich, Munich, Germany"},{"name":"Institute for Advanced Study, Technical University of Munich, Garching, Germany"},{"name":"Institute of Neurogenomics, Helmholtz Zentrum M\u00fcnchen, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2025,3,27]]},"reference":[{"key":"2025101714310436000_62.6.388.1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(20)30312-4"},{"key":"2025101714310436000_62.6.388.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2019.11.004"},{"key":"2025101714310436000_62.6.388.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2020.04.003"},{"key":"2025101714310436000_62.6.388.4","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathmechdis-051122-110756"},{"key":"2025101714310436000_62.6.388.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-023-00909-9"},{"key":"2025101714310436000_62.6.388.6","doi-asserted-by":"publisher","DOI":"10.1002\/mds.30037"},{"key":"2025101714310436000_62.6.388.7","doi-asserted-by":"publisher","DOI":"10.1016\/bs.irn.2023.04.009"},{"key":"2025101714310436000_62.6.388.8","doi-asserted-by":"publisher","DOI":"10.1002\/mds.28804"},{"key":"2025101714310436000_62.6.388.9","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gki033"},{"key":"2025101714310436000_62.6.388.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2014.12.009"},{"key":"2025101714310436000_62.6.388.11","doi-asserted-by":"publisher","DOI":"10.2174\/0929866043406643"},{"key":"2025101714310436000_62.6.388.12","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky930"},{"key":"2025101714310436000_62.6.388.13","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-007-9356-3"},{"key":"2025101714310436000_62.6.388.14","doi-asserted-by":"publisher","DOI":"10.1111\/febs.14009"},{"key":"2025101714310436000_62.6.388.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2023.102337"},{"key":"2025101714310436000_62.6.388.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2022.03.007"},{"key":"2025101714310436000_62.6.388.17","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-01910-8"},{"key":"2025101714310436000_62.6.388.18","doi-asserted-by":"publisher","DOI":"10.1038\/538161a"},{"key":"2025101714310436000_62.6.388.19","doi-asserted-by":"publisher","DOI":"10.1002\/mdc3.13165"},{"key":"2025101714310436000_62.6.388.20","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-024-00776-0"},{"key":"2025101714310436000_62.6.388.21","doi-asserted-by":"crossref","unstructured":"Fellner A , Wali GM , Mahant N , et al . Genome sequencing reanalysis increases the diagnostic yield in dystonia. Parkinsonism Relat Disord 2024;124. doi:10.1016\/j.parkreldis.2024.107010","DOI":"10.1016\/j.parkreldis.2024.107010"},{"key":"2025101714310436000_62.6.388.22","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22844"},{"key":"2025101714310436000_62.6.388.23","doi-asserted-by":"publisher","DOI":"10.1002\/mds.28928"},{"key":"2025101714310436000_62.6.388.24","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1002\/mds.29021","article-title":"Expanded Genetic Spectrum and Variable Disease Onset in AOPEP-Associated Dystonia","volume":"37","author":"Menden","year":"2022","journal-title":"Mov Disord"},{"key":"2025101714310436000_62.6.388.25","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-023-11665-7"},{"key":"2025101714310436000_62.6.388.26","doi-asserted-by":"publisher","DOI":"10.1002\/mds.29629"},{"key":"2025101714310436000_62.6.388.27","doi-asserted-by":"publisher","DOI":"10.1136\/jmg-2022-109099"},{"key":"2025101714310436000_62.6.388.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2021.08.009"},{"key":"2025101714310436000_62.6.388.29","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw1099"},{"key":"2025101714310436000_62.6.388.30","doi-asserted-by":"publisher","DOI":"10.1002\/mds.29327"},{"key":"2025101714310436000_62.6.388.31","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"2025101714310436000_62.6.388.32","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3740"},{"key":"2025101714310436000_62.6.388.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2017.12.015"},{"key":"2025101714310436000_62.6.388.34","doi-asserted-by":"publisher","DOI":"10.1002\/mds.27442"},{"key":"2025101714310436000_62.6.388.35","doi-asserted-by":"publisher","DOI":"10.1002\/mds.27638"},{"key":"2025101714310436000_62.6.388.36","doi-asserted-by":"publisher","DOI":"10.1002\/mds.28485"},{"key":"2025101714310436000_62.6.388.37","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-023-00574-0"},{"key":"2025101714310436000_62.6.388.38","doi-asserted-by":"publisher","DOI":"10.1002\/mds.30066"},{"key":"2025101714310436000_62.6.388.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2024.11.004"},{"key":"2025101714310436000_62.6.388.40","doi-asserted-by":"publisher","DOI":"10.1007\/s10741-007-9078-2"},{"key":"2025101714310436000_62.6.388.41","doi-asserted-by":"publisher","DOI":"10.1002\/pro.3307"},{"key":"2025101714310436000_62.6.388.42","doi-asserted-by":"publisher","DOI":"10.1038\/nature24277"},{"key":"2025101714310436000_62.6.388.43","doi-asserted-by":"publisher","DOI":"10.1002\/mds.28892"},{"key":"2025101714310436000_62.6.388.44","doi-asserted-by":"crossref","DOI":"10.3389\/fmolb.2020.583556","article-title":"The Role of Insulin Regulated Aminopeptidase in Endocytic Trafficking and Receptor Signaling in Immune Cells","volume":"7","author":"Descamps","year":"2020","journal-title":"Front Mol Biosci"},{"key":"2025101714310436000_62.6.388.45","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab161"},{"key":"2025101714310436000_62.6.388.46","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.6.2727"},{"key":"2025101714310436000_62.6.388.47","doi-asserted-by":"crossref","unstructured":"Blackburn PR , Ebstein F , Hsieh T-C , et al . Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder. Ann Neurol 2024. doi:10.1002\/ana.27077","DOI":"10.1002\/ana.27077"},{"key":"2025101714310436000_62.6.388.48","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.51335"},{"key":"2025101714310436000_62.6.388.49","doi-asserted-by":"crossref","DOI":"10.1093\/braincomms\/fcab197","article-title":"Levodopa-responsive dystonia caused by biallelic PRKN exon inversion invisible to exome sequencing","volume":"3","author":"Mor-Shaked","year":"2021","journal-title":"Brain Commun"},{"key":"2025101714310436000_62.6.388.50","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-020-10395-4"},{"key":"2025101714310436000_62.6.388.51","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2024.11.009"},{"key":"2025101714310436000_62.6.388.52","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000202396"},{"key":"2025101714310436000_62.6.388.53","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-56867-x"},{"key":"2025101714310436000_62.6.388.54","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-025-56782-1","article-title":"Loss-of-function mutations in the dystonia gene THAP1 impair proteasome function by inhibiting PSMB5 expression","volume":"16","author":"Ramage","year":"2025","journal-title":"Nat Commun"},{"key":"2025101714310436000_62.6.388.55","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2017.04.003"},{"key":"2025101714310436000_62.6.388.56","doi-asserted-by":"crossref","DOI":"10.3389\/fphar.2020.585930","article-title":"IRAP Inhibitors: M1-Aminopeptidase Family Inspiration","volume":"11","author":"Barlow","year":"2020","journal-title":"Front Pharmacol"}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmg-2025-110656","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T21:31:14Z","timestamp":1760736674000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmg-2025-110656"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,27]]},"references-count":56,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,5,27]]},"published-print":{"date-parts":[[2025,6]]}},"alternative-id":["10.1136\/jmg-2025-110656"],"URL":"https:\/\/doi.org\/10.1136\/jmg-2025-110656","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"value":"0022-2593","type":"print"},{"value":"1468-6244","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,27]]}}}