PUBLICATION
Gaucher disease protects against tuberculosis
- Authors
- Fan, J., Hale, V.L., Lelieveld, L.T., Whitworth, L.J., Busch-Nentwich, E.M., Troll, M., Edelstein, P.H., Cox, T.M., Roca, F.J., Aerts, J.M.F.G., Ramakrishnan, L.
- ID
- ZDB-PUB-230207-24
- Date
- 2023
- Source
- Proceedings of the National Academy of Sciences of the United States of America 120: e2217673120e2217673120 (Journal)
- Registered Authors
- Busch-Nentwich, Elisabeth, Roca, Francisco Jose
- Keywords
- Gaucher disease, lysosomal glucosylsphingosine, macrophages, tuberculosis resistance, zebrafish
- MeSH Terms
-
- Animals
- Gaucher Disease*/genetics
- Glucosylceramidase/genetics
- Mutation
- Tuberculosis*/genetics
- Tuberculosis*/prevention & control
- Zebrafish/genetics
- PubMed
- 36745788 Full text @ Proc. Natl. Acad. Sci. USA
Citation
Fan, J., Hale, V.L., Lelieveld, L.T., Whitworth, L.J., Busch-Nentwich, E.M., Troll, M., Edelstein, P.H., Cox, T.M., Roca, F.J., Aerts, J.M.F.G., Ramakrishnan, L. (2023) Gaucher disease protects against tuberculosis. Proceedings of the National Academy of Sciences of the United States of America. 120:e2217673120e2217673120.
Abstract
Biallelic mutations in the glucocerebrosidase (GBA1) gene cause Gaucher disease, characterized by lysosomal accumulation of glucosylceramide and glucosylsphingosine in macrophages. Gaucher and other lysosomal diseases occur with high frequency in Ashkenazi Jews. It has been proposed that the underlying mutations confer a selective advantage, in particular conferring protection against tuberculosis. Here, using a zebrafish Gaucher disease model, we find that the mutation GBA1 N370S, predominant among Ashkenazi Jews, increases resistance to tuberculosis through the microbicidal activity of glucosylsphingosine in macrophage lysosomes. Consistent with lysosomal accumulation occurring only in homozygotes, heterozygotes remain susceptible to tuberculosis. Thus, our findings reveal a mechanistic basis for protection against tuberculosis by GBA1 N370S and provide biological plausibility for its selection if the relatively mild deleterious effects in homozygotes were offset by significant protection against tuberculosis, a rampant killer of the young in Europe through the Middle Ages into the 19th century.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping