| Title: | African ancestry neurodegeneration risk variant disrupts an intronic branchpoint in GBA1 |
| Journal: | Nature Structural & Molecular Biology |
| Published: | 12 Dec 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39668204/ |
| DOI: | https://doi.org/10.1038/s41594-024-01423-2 |
Publication 14000
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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.</p>
8 Keywords
- Black People
- Genetic Predisposition to Disease
- Glucosylceramidase
- Humans
- Introns
- Parkinson Disease
- Polymorphism, Single Nucleotide
- RNA Splicing
40 Authors
- Pilar Álvarez Jerez
- Peter Wild Crea
- Daniel M. Ramos
- Emil K. Gustavsson
- Mandy Radefeldt
- Andrey Damianov
- Mary B. Makarious
- Oluwadamilola O. Ojo
- Kimberley J. Billingsley
- Laksh Malik
- Kensuke Daida
- Sarah Bromberek
- Fangle Hu
- Zachary Schneider
- Aditya L. Surapaneni
- Julia Stadler
- Mie Rizig
- Huw R. Morris
- Caroline B. Pantazis
- Hampton L. Leonard
- Laurel Screven
- Yue A. Qi
- Mike A. Nalls
- Sara Bandres-Ciga
- John Hardy
- Henry Houlden
- Celeste Eng
- Esteban González Burchard
- Linda Kachuri
- Chia-Ho Lin
- Douglas L. Black
- Andrew B. Singleton
- Steffen Fischer
- Peter Bauer
- Xylena Reed
- Mina Ryten
- Christian Beetz
- Michael Ward
- Njideka U. Okubadejo
- Cornelis Blauwendraat
1 Application
| Application ID | Title |
|---|---|
| 33601 | Dissecting the genetic architecture of neurodegenerative diseases |
Enabling scientific discoveries that improve human health