{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T11:02:57Z","timestamp":1775991777768,"version":"3.50.1"},"posted":{"date-parts":[[2025,6,15]]},"group-title":"Genomics","reference-count":25,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,15]],"date-time":"2025-06-15T00:00:00Z","timestamp":1749945600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"crossref","award":["ZIAAG000534"],"award-info":[{"award-number":["ZIAAG000534"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["ZIAAG000535"],"award-info":[{"award-number":["ZIAAG000535"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,6,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  <jats:italic>GBA1<\/jats:italic>\n                  is a risk gene for multiple neurodegenerative diseases, including Lewy Body Dementia and Parkinson\u2019s disease, and biallelic pathogenic variants in the gene result in the lysosomal storage disorder Gaucher disease.\n                  <jats:italic>GBA1<\/jats:italic>\n                  encodes the enzyme glucocerebrosidase (GCase), and alterations in the gene result in reduced enzymatic activity, which affects lysosome function downstream. Induced pluripotent stem cells (iPSCs) are a useful tool for testing the functional consequences of gene variants in an isogenic setting. Additionally, they can be used to perform multiomic studies to explore biological effects independent of disease mechanisms. Using CRISPR-edited isogenic KOLF2.1J iPSC lines containing pathogenic\n                  <jats:italic>GBA1<\/jats:italic>\n                  variants D409H (p.D448H), D409V (p.D448V) and GBA1 knockout line generated by the iPSC Neurodegenerative Disease Initiative (iNDI), we examined potential molecular mechanisms and downstream consequences of GCase reduction. In this study, we confirm that this isogenic series behaves as expected for loss of function variants, despite the known difficulties with\n                  <jats:italic>GBA1<\/jats:italic>\n                  editing. We identified that there are limited overlapping results across cell types suggesting potential different downstream effects caused by\n                  <jats:italic>GBA1<\/jats:italic>\n                  variants. Additionally, we note that RNA-based quantitation may not be the best method to characterize GCase mechanisms, but protein and metabolomic analyses may be used to evaluate differences across genotypes.\n                <\/jats:p>","DOI":"10.1101\/2025.06.12.656971","type":"posted-content","created":{"date-parts":[[2025,6,15]],"date-time":"2025-06-15T12:50:11Z","timestamp":1749991811000},"source":"Crossref","is-referenced-by-count":1,"title":["Dissecting the biological impact of\n                  <i>GBA1<\/i>\n                  mutations using multi-omics in an isogenic setting"],"prefix":"10.64898","author":[{"given":"Pilar \u00c1lvarez","family":"Jerez","sequence":"first","affiliation":[{"name":"Center for Alzheimer\u2019s and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA"},{"name":"Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA"},{"name":"Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter A.","family":"Wild Crea","sequence":"additional","affiliation":[{"name":"Center for Alzheimer\u2019s and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dhairya","family":"Patel","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Logan M.","family":"Glasstetter","sequence":"additional","affiliation":[{"name":"Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christiane","family":"Alvarez","sequence":"additional","affiliation":[{"name":"Center for Alzheimer\u2019s and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7978-1051","authenticated-orcid":false,"given":"Mary B.","family":"Makarious","sequence":"additional","affiliation":[{"name":"Center for Alzheimer\u2019s and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA"},{"name":"Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA"},{"name":"DataTecnica LLC, Washington, DC, 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USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kimberly","family":"Paquette","sequence":"additional","affiliation":[{"name":"Center for Alzheimer\u2019s and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laksh","family":"Malik","sequence":"additional","affiliation":[{"name":"Center for Alzheimer\u2019s and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mike A.","family":"Nalls","sequence":"additional","affiliation":[{"name":"Center for Alzheimer\u2019s and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 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