African ancestry neurodegeneration risk variant disrupts an intronic branchpoint in GBA1

Recently, an African ancestry-specific Parkinson disease (PD) risk signal was identified at the gene encoding glucocerebrosidase (GBA1). This variant ( rs3115534 -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. GBA1 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 GBA1 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 ( rs3115534 ) 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 GBA1 noncoding risk variant, which acts by interfering with the splicing of functional GBA1 transcripts, resulting in reduced protein levels and reduced glucocerebrosidase activity. This understanding reveals a potential therapeutic target in an underserved and underrepresented population.

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Publication Details

Journal
Nature Structural & Molecular Biology
Published
2024-12-01
DOI
https://doi.org/10.1038/s41594-024-01423-2
Citations
12
Primary Topic
Lysosomal Storage Disorders Research
Type
article
Field-Weighted Citation Impact
3.92

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article

African ancestry neurodegeneration risk variant disrupts an intronic branchpoint in GBA1

Julia T. Stadler, John Hardy, Peter Wild Crea, Pilar Álvarez Jerez et al.
12 citations
Nature Structural & Molecular Biology
Lysosomal Storage Disorders Research
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article

African ancestry neurodegeneration risk variant disrupts an intronic branchpoint in GBA1

Julia T. Stadler, John Hardy, Peter Wild Crea, Pilar Álvarez Jerez, Michael Emmerson Ward, Hampton L. Leonard, Aditya Surapaneni, Yue Qi, Mike A. Nalls, Sara Bandrés‐Ciga, Mina Ryten, Mary B. Makarious, Laurel A. Screven, Laksh Malik, Oluwadamilola O. Ojo, Xylena Reed, Chia-Ho Lin, Linda Kachuri, Kensuke Daida, Andrey Damianov, Mandy Radefeldt, Douglas L. Black, Emil Karl Gustavsson, Cornelis Blauwendraat, Mie Rizig, Zachary Schneider, Esteban G. Burchard, Njideka Ulunma Okubadejo, Huw R. Morris, Henry Houlden, Fangle Hu, Caroline B. Pantazis, Peter Bauer, Christian Beetz, Celeste Eng, Daniel M. Ramos, Steffen Fischer, Andrew B. Singleton, Kimberley J. Billingsley, Sarah Bromberek
article en
12 citations

Abstract

Recently, an African ancestry-specific Parkinson disease (PD) risk signal was identified at the gene encoding glucocerebrosidase (GBA1). This variant ( rs3115534 -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. GBA1 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 GBA1 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 ( rs3115534 ) 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 GBA1 noncoding risk variant, which acts by interfering with the splicing of functional GBA1 transcripts, resulting in reduced protein levels and reduced glucocerebrosidase activity. This understanding reveals a potential therapeutic target in an underserved and underrepresented population.

Nature Structural & Molecular BiologyVol. 31(12)
National Institutes of Health (US), University of California, Los Angeles (US), University of California, San Francisco (US), University of Lagos (NG), University of Cambridge (GB), Great Ormond Street Hospital (GB), Lagos University Teaching Hospital (NG), NYU Langone Health (US), National Institute of Neurological Disorders and Stroke (US), UK Dementia Research Institute (GB), National Institute on Aging (US), Centogene (Germany) (DE), National Hospital for Neurology and Neurosurgery (GB), Research Network (United States) (US), University College London (GB), Stanford University (US)
Michael J. Fox Foundation for Parkinson's Research, National Institutes of Health, National Institute of Neurological Disorders and Stroke
Good health and well-being
Openalex Percentile: Top 5%
Lysosomal Storage Disorders Research
3.92
DOIOpen Access PDFOpenAlex
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