TY - JOUR
T1 - The annotation of GBA1 has been concealed by its protein-coding pseudogene GBAP1
AU - Gustavsson, Emil K.
AU - Sethi, Siddharth
AU - Gao, Yujing
AU - Brenton, Jonathan W.
AU - García-Ruiz, Sonia
AU - Zhang, David
AU - Garza, Raquel
AU - Reynolds, Regina H.
AU - Evans, James R.
AU - Chen, Zhongbo
AU - Grant-Peters, Melissa
AU - Macpherson, Hannah
AU - Montgomery, Kylie
AU - Dore, Rhys
AU - Wernick, Anna i.
AU - Arber, Charles
AU - Wray, Selina
AU - Gandhi, Sonia
AU - Esselborn, Julian
AU - Blauwendraat, Cornelis
AU - Douse, Christopher H.
AU - Adami, Anita
AU - Atacho, Diahann A. M.
AU - Kouli, Antonina
AU - Quaegebeur, Annelies
AU - Barker, Roger A.
AU - Englund, Elisabet
AU - Platt, Frances
AU - Jakobsson, Johan
AU - Wood, Nicholas W.
AU - Houlden, Henry
AU - Saini, Harpreet
AU - Bento, Carla F.
AU - Hardy, John
AU - Ryten, Mina
PY - 2024/6/28
Y1 - 2024/6/28
N2 - 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.
AB - 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.
U2 - 10.1126/sciadv.adk1296
DO - 10.1126/sciadv.adk1296
M3 - Article
C2 - 38924406
SN - 2375-2548
VL - 10
JO - Science Advances
JF - Science Advances
IS - 26
M1 - eadk1296
ER -