The annotation of <i>GBA1</i> has been concealed by its protein-coding pseudogene <i>GBAP1</i>-Reference-Cited by-同舟云学术

The annotation of GBA1 has been concealed by its protein-coding pseudogene GBAP1

Published:2024-06-28 Issue:26 Volume:10 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Gustavsson Emil K.¹²^ORCID,Sethi Siddharth¹³^ORCID,Gao Yujing³^ORCID,Brenton Jonathan W.¹²^ORCID,García-Ruiz Sonia¹⁴^ORCID,Zhang David¹,Garza Raquel⁵^ORCID,Reynolds Regina H.¹²^ORCID,Evans James R.²⁶⁷^ORCID,Chen Zhongbo⁸^ORCID,Grant-Peters Melissa¹²^ORCID,Macpherson Hannah⁸^ORCID,Montgomery Kylie¹⁸^ORCID,Dore Rhys¹^ORCID,Wernick Anna I.⁶⁷^ORCID,Arber Charles⁸^ORCID,Wray Selina⁸,Gandhi Sonia²⁶⁷^ORCID,Esselborn Julian³^ORCID,Blauwendraat Cornelis⁹^ORCID,Douse Christopher H.¹⁰^ORCID,Adami Anita⁵^ORCID,Atacho Diahann A. M.⁵^ORCID,Kouli Antonina¹¹^ORCID,Quaegebeur Annelies²¹²,Barker Roger A.²¹¹^ORCID,Englund Elisabet¹³^ORCID,Platt Frances²¹⁴,Jakobsson Johan²⁵^ORCID,Wood Nicholas W.²⁶^ORCID,Houlden Henry¹⁵^ORCID,Saini Harpreet³,Bento Carla F.³^ORCID,Hardy John²⁸¹⁶¹⁷¹⁸^ORCID,Ryten Mina¹²⁴^ORCID

Affiliation:

1. Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK.

2. Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA.

3. Astex Pharmaceuticals, 436 Cambridge Science Park, Cambridge, UK.

4. NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK.

5. Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund, Sweden.

6. Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK.

7. The Francis Crick Institute, London, UK.

8. Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK.

9. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.

10. Laboratory of Epigenetics and Chromatin Dynamics, Department of Experimental Medical Science, Lund Stem Cell Center, Lund University, Lund, Sweden.

11. Wellcome-MRC Cambridge Stem Cell Institute and John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

12. Department of Clinical Neurosciences, University of Cambridge, Clifford Albutt Building, Cambridge, UK.

13. Department of Neuropathology, University of Lund, Lund, Sweden.

14. Department of Pharmacology, University of Oxford, Oxford, UK.

15. Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology, UCL, London, UK.

16. Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, UCL, London, UK.

17. UK Dementia Research Institute at UCL, UCL Queen Square Institute of Neurology, UCL, London, UK.

18. NIHR University College London Hospitals Biomedical Research Centre, London, UK.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/sciadv.adk1296

Reference82 articles.

1. Systematic analysis of dark and camouflaged genes reveals disease-relevant genes hiding in plain sight

2. The GENCODE pseudogene resource

3. Comprehensive short and long read sequencing analysis for the Gaucher and Parkinson’s disease-associated GBA gene

4. Handling multi-mapped reads in RNA-seq

5. The lysosomal localization of sphingolipid hydrolases

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