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Hillblom Foundation","doi-asserted-by":"publisher","award":["2016\u2010A\u2010005\u2010SUP"],"award-info":[{"award-number":["2016\u2010A\u2010005\u2010SUP"]}],"id":[{"id":"10.13039\/100001167","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000957","name":"Alzheimer's Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015442","name":"Global Brain Health Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015442","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>INTRODUCTION<\/jats:title>\n                    <jats:p>Variants of uncertain significance (VUS) surged with affordable genetic testing, posing challenges for determining pathogenicity. We examine the pathogenicity of a novel VUS P93S in Annexin A11 (ANXA11) \u2013 an amyotrophic lateral sclerosis\/frontotemporal dementia\u2010associated gene \u2013 in a corticobasal syndrome kindred. Established ANXA11 mutations cause ANXA11 aggregation, altered lysosomal\u2010RNA granule co\u2010trafficking, and transactive response DNA binding protein of 43 kDa (TDP\u201043) mis\u2010localization.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>We described\u00a0the clinical presentation and explored the phenotypic diversity of ANXA11 variants. P93S's effect on ANXA11 function and TDP\u201043 biology was characterized in induced pluripotent stem cell\u2010derived neurons alongside multiomic neuronal and microglial profiling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>ANXA11 mutations were linked to corticobasal syndrome cases. P93S led to decreased lysosome colocalization, neuritic RNA, and nuclear TDP\u201043 with cryptic exon expression. Multiomic microglial signatures implicated immune dysregulation and interferon signaling pathways.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>This study establishes ANXA11 P93S pathogenicity, broadens the phenotypic spectrum of ANXA11 mutations, underscores neuronal and microglial dysfunction in ANXA11 pathophysiology, and demonstrates the potential of cellular models to determine variant pathogenicity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            <jats:italic>ANXA11<\/jats:italic>\n                            P93S is a pathogenic variant.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Corticobasal syndrome is part of the\n                            <jats:italic>ANXA11<\/jats:italic>\n                            phenotypic spectrum.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Hybridization chain reaction fluorescence in situ hybridization (HCR FISH) is a new tool for the detection of cryptic exons due to TDP\u201043\u2010related loss of splicing regulation.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Microglial ANXA11 and related immune pathways are important drivers of disease.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Cellular models are powerful tools for adjudicating variants of uncertain significance.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.13915","type":"journal-article","created":{"date-parts":[[2024,6,26]],"date-time":"2024-06-26T03:21:49Z","timestamp":1719372109000},"page":"5220-5235","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["An\n                    <i>ANXA11<\/i>\n                    P93S variant dysregulates TDP\u201043 and causes corticobasal syndrome"],"prefix":"10.1002","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1857-928X","authenticated-orcid":false,"given":"Allison","family":"Snyder","sequence":"first","affiliation":[{"name":"Neurogenetics Branch National Institute of Neurological Disorders and Stroke National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica H.","family":"Ryan","sequence":"additional","affiliation":[{"name":"Center for Alzheimer's and Related Dementias National Institutes of Health  Bethesda Maryland USA"},{"name":"National Institute of General Medical Sciences National Institutes of Health Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Hawrot","sequence":"additional","affiliation":[{"name":"Neurogenetics Branch National Institute of Neurological Disorders and Stroke National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney","family":"Lawton","sequence":"additional","affiliation":[{"name":"Neurogenetics Branch National Institute of Neurological Disorders and Stroke National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel M.","family":"Ramos","sequence":"additional","affiliation":[{"name":"Center for Alzheimer's and Related Dementias National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y. 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