{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T01:14:48Z","timestamp":1788570888440,"version":"build-2803163510"},"reference-count":27,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T00:00:00Z","timestamp":1753833600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000582","name":"Carnegie Trust for the Universities of Scotland","doi-asserted-by":"publisher","award":["PHD010656"],"award-info":[{"award-number":["PHD010656"]}],"id":[{"id":"10.13039\/501100000582","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000589","name":"Chief Scientist Office","doi-asserted-by":"publisher","award":["SCAF\/18\/01"],"award-info":[{"award-number":["SCAF\/18\/01"]}],"id":[{"id":"10.13039\/501100000589","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["movementdisorders.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Movement Disorders"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Gain\u2010of\u2010kinase\u2010function variants in LRRK2 are a leading cause of monogenic Parkinson's disease (PD).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>We tested the functional impact of a novel LRRK2 variant p.V1447L identified in a young\u2010onset PD patient in vivo in peripheral blood, as well as in a robust cellular assay, alongside other variants in close proximity to V1447.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We measured LRRK2\u2010dependent Rab10 phosphorylation in neutrophils and monocytes of a LRRK2 p.V1447L carrier with PD. We performed structural mapping and evaluated the potential impact of other LRRK2 variants at and around LRRK2 V1447.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      LRRK2 p.V1447L strongly increases LRRK2 kinase activity. We identified additional variants in the LRRK2 ROC:COR\n                      <jats:sub>B<\/jats:sub>\n                      interface with critical impact on kinase activity and demonstrated that different substitutions at the same residue can have opposing effects.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      We recommend reclassifying LRRK2 p.V1447L from variant of uncertain significance to likely pathogenic. Our study expands the range of putative loss\u2010of\u2010kinase function variants to LRRK2 missense variants. \u00a9 2025 The Author(s).\n                      <jats:italic>Movement Disorders<\/jats:italic>\n                      published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/mds.30284","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T09:45:08Z","timestamp":1753868708000},"page":"2251-2256","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Functional and Structural Characterization of\n                    <scp>LRRK2<\/scp>\n                    p.\n                    <scp>V1447L<\/scp>\n                    in Parkinson's Disease"],"prefix":"10.1002","volume":"40","author":[{"given":"Neringa","family":"Pratuseviciute","sequence":"first","affiliation":[{"name":"Medical Research Council Protein Phosphorylation and Ubiquitylation Unit University of Dundee  Dundee UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4978-7671","authenticated-orcid":false,"given":"Pawel","family":"Lis","sequence":"additional","affiliation":[{"name":"Medical Research Council Protein Phosphorylation and Ubiquitylation Unit University of Dundee  Dundee UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sacha","family":"Weber","sequence":"additional","affiliation":[{"name":"Institut du Cerveau\u2010Paris Brain Institute ICM Sorbonne Universit\u00e9, Inserm 1127, CNRS 7225, H\u00f4pital de la Piti\u00e9 Salp\u00eatri\u00e8re  Paris 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