{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T05:01:02Z","timestamp":1792213262783,"version":"4.4.0"},"reference-count":45,"publisher":"Springer Science and Business Media LLC","issue":"12","license":[{"start":{"date-parts":[[2024,12,1]],"date-time":"2024-12-01T00:00:00Z","timestamp":1733011200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T00:00:00Z","timestamp":1733961600000},"content-version":"vor","delay-in-days":11,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Struct Mol Biol"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Recently, an African ancestry-specific Parkinson disease (PD) risk signal was identified at the gene encoding glucocerebrosidase (\n                    <jats:italic>GBA1<\/jats:italic>\n                    ). This variant (\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.ncbi.nlm.nih.gov\/snp\/?term=rs3115534\">rs3115534<\/jats:ext-link>\n                    -G) is carried by ~50% of West African PD cases and imparts a dose-dependent increase in risk for disease. The risk variant has varied frequencies across African ancestry groups but is almost absent in European and Asian ancestry populations.\n                    <jats:italic>GBA1<\/jats:italic>\n                    is a gene of high clinical and therapeutic interest. Damaging biallelic protein-coding variants cause Gaucher disease and monoallelic variants confer risk for PD and dementia with Lewy bodies, likely by reducing the function of glucocerebrosidase. Interestingly, the African ancestry-specific\n                    <jats:italic>GBA1<\/jats:italic>\n                    risk variant is a noncoding variant, suggesting a different mechanism of action. Using full-length RNA transcript sequencing, we identified partial intron 8 expression in risk variant carriers (G) but not in nonvariant carriers (T). Antibodies targeting the N terminus of glucocerebrosidase showed that this intron-retained isoform is likely not protein coding and subsequent proteomics did not identify a shorter protein isoform, suggesting that the disease mechanism is RNA based. Clustered regularly interspaced short palindromic repeats editing of the reported index variant (\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.ncbi.nlm.nih.gov\/snp\/?term=rs3115534\">rs3115534<\/jats:ext-link>\n                    ) revealed that this is the sequence alteration responsible for driving the production of these transcripts containing intron 8. Follow-up analysis of this variant showed that it is in a key intronic branchpoint sequence and, therefore, has important implications in splicing and disease. In addition, when measuring glucocerebrosidase activity, we identified a dose-dependent reduction in risk variant carriers. Overall, we report the functional effect of a\n                    <jats:italic>GBA1<\/jats:italic>\n                    noncoding risk variant, which acts by interfering with the splicing of functional\n                    <jats:italic>GBA1<\/jats:italic>\n                    transcripts, resulting in reduced protein levels and reduced glucocerebrosidase activity. This understanding reveals a potential therapeutic target in an underserved and underrepresented population.\n                  <\/jats:p>","DOI":"10.1038\/s41594-024-01423-2","type":"journal-article","created":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T11:01:58Z","timestamp":1734001318000},"page":"1955-1963","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["African ancestry neurodegeneration risk variant disrupts an intronic branchpoint in GBA1"],"prefix":"10.1038","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5812-1898","authenticated-orcid":false,"given":"Pilar","family":"\u00c1lvarez Jerez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8944-5716","authenticated-orcid":false,"given":"Peter","family":"Wild 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