The annotation of GBA1 has been concealed by its protein-coding pseudogene GBAP1
Open accessPublished version of a preprint
Abstract
Mutations in GBA1 cause Gaucher disease and are the most important genetic risk factor for Parkinson’s disease. However, analysis of transcription at this locus is complicated by its highly homologous pseudogene, GBAP1 . We show that >50% of short RNA-sequencing reads mapping to GBA1 also map to GBAP1 . Thus, we used long-read RNA sequencing in the human brain, which allowed us to accurately quantify expression from both GBA1 and GBAP1 . We discovered significant differences in expression compared to short-read data and identify currently unannotated transcripts of both GBA1 and GBAP1 . These included protein-coding transcripts from both genes that were translated in human brain, but without the known lysosomal function—yet accounting for almost a third of transcription. Analyzing brain-specific cell types using long-read and single-nucleus RNA sequencing revealed region-specific variations in transcript expression. Overall, these findings suggest nonlysosomal roles for GBA1 and GBAP1 with implications for our understanding of the role of GBA1 in health and disease.
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Flagged first, then by citations
- Authors
- Gustavsson, E. K., Sethi, S., Gao, Y., Brenton, J. W., García-Ruiz, S., Zhang, D., Garza, R., Reynolds, R. H., Evans, J. R., Chen, Z., Grant-Peters, M., Macpherson, H., Montgomery, K., Dore, R., Wernick, A. I., Arber, C., Wray, S., Gandhi, S., Esselborn, J., Blauwendraat, C., Douse, C. H., Adami, A., Atacho, D. A. M., Kouli, A., Quaegebeur, A., Barker, R. A., Englund, E., Platt, F., Jakobsson, J., Wood, N. W., Houlden, H., Saini, H., Bento, C. F., Hardy, J., & Ryten, M.
- Affiliations
- Aligning Science Across Parkinson's (US)
- University College London (GB)
- Astex Pharmaceuticals, 436 Cambridge Science Park, Cambridge, UK.
- NIHR Great Ormond Street Hospital Biomedical Research Centre (GB)
- Lund University (SE)
- The Francis Crick Institute (GB)
- UCL Queen Square Institute of Neurology (GB)
- Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK.
- National Institutes of Health (US)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University of Cambridge (GB)
- University of Oxford (GB)
- Hong Kong University of Science and Technology (HK)
- Corresponding author
- Ryten, Mina
- ORCID
- Gustavsson, Emil K.
- Sethi, Siddharth
- Gao, Yujing
- Brenton, Jonathan W.
- García-Ruiz, Sonia
- Zhang, David
- Garza, Raquel
- Reynolds, Regina H.
- Evans, James R.
- Chen, Zhongbo
- Grant-Peters, Melissa
- Macpherson, Hannah
- Montgomery, Kylie
- Dore, Rhys
- Wernick, Anna I.
- Arber, Charles
- Wray, Selina
- Gandhi, Sonia
- Esselborn, Julian
- Blauwendraat, Cornelis
- Douse, Christopher H.
- Adami, Anita
- Atacho, Diahann A. M.
- Kouli, Antonina
- Quaegebeur, Annelies
- Barker, Roger A.
- Englund, Elisabet
- Platt, Frances
- Jakobsson, Johan
- Wood, Nicholas W.
- Houlden, Henry
- Saini, Harpreet
- Bento, Carla F.
- Hardy, John
- Ryten, Mina
- Venue
- Science Advances
- Published
- 2024-06-28
- Volume
- 10
- Issue
- 26
- Pages
- eadk1296-eadk1296
- ISSN
- 2375-2548 (ISSN-L)
- PMC
- PMC11204300
- OpenAlex
- W4400033871
- Cited by
- 30
- References
- 9
- Citations by year
- 2026: 4 · 2025: 17 · 2024: 7 · 2023: 2
- FWCI
- 7.97
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- Science Advances (publishedVersion, cc-by-nc)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- Michael J. Fox Foundation for Parkinson's Research (ASAP-000478, ASAP-000509)
- BrightFocus Foundation (A2021009F)
- Astex Pharmaceuticals
- Alzheimer's Society (AS‐JF‐18‐008)
- National Institute for Health and Care Research
- Svenska Sällskapet för Medicinsk Forskning (S19‐0100)
- Medical Research Council (MR/W031485/1, MC_PC_17230, MR/T008199/1)
- Topics
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
- Keywords
- GBA1, pseudogenes, genome annotation, Gaucher disease, Parkinson's disease, transcriptome, long-read RNA sequencing, single-nucleus RNA sequencing, brain cell types, lysosomal genes
- MeSH terms
- Brain, Gaucher Disease, Glucosylceramidase, Humans, Parkinson Disease, Pseudogenes, Sequence Analysis, RNA, Molecular Sequence Annotation
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