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

Gustavsson, Emil K. ; Sethi, Siddharth ; Gao, Yujing ; Brenton, Jonathan W. ; García-Ruiz, Sonia ; Zhang, David ; Garza, Raquel LU orcid ; Reynolds, Regina H. ; Evans, James R. and Chen, Zhongbo , et al. (2024) In Science Advances 10(26). p.1-20
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Science Advances
volume
10
issue
26
pages
1 - 20
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • pmid:38924406
ISSN
2375-2548
DOI
10.1126/sciadv.adk1296
language
English
LU publication?
yes
id
1bd86ba8-32fe-42f2-bfc1-db96a69ef7ac
date added to LUP
2024-06-28 11:22:39
date last changed
2024-07-01 09:02:40
@article{1bd86ba8-32fe-42f2-bfc1-db96a69ef7ac,
  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.}},
  author       = {{Gustavsson, Emil K. and Sethi, Siddharth and Gao, Yujing and Brenton, Jonathan W. and García-Ruiz, Sonia and Zhang, David and Garza, Raquel and Reynolds, Regina H. and Evans, James R. and Chen, Zhongbo and Grant-Peters, Melissa and Macpherson, Hannah and Montgomery, Kylie and Dore, Rhys and Wernick, Anna i. and Arber, Charles and Wray, Selina and Gandhi, Sonia and Esselborn, Julian and Blauwendraat, Cornelis and Douse, Christopher H. and Adami, Anita and Atacho, Diahann A. M. and Kouli, Antonina and Quaegebeur, Annelies and Barker, Roger A. and Englund, Elisabet and Platt, Frances and Jakobsson, Johan and Wood, Nicholas W. and Houlden, Henry and Saini, Harpreet and Bento, Carla F. and Hardy, John and Ryten, Mina}},
  issn         = {{2375-2548}},
  language     = {{eng}},
  month        = {{06}},
  number       = {{26}},
  pages        = {{1--20}},
  publisher    = {{American Association for the Advancement of Science (AAAS)}},
  series       = {{Science Advances}},
  title        = {{The annotation of GBA1 has been concealed by its protein-coding pseudogene GBAP1}},
  url          = {{http://dx.doi.org/10.1126/sciadv.adk1296}},
  doi          = {{10.1126/sciadv.adk1296}},
  volume       = {{10}},
  year         = {{2024}},
}