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Gaucher disease protects against tuberculosis.

Published version
Peer-reviewed

Type

Article

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Authors

Fan, Jingwen 
Hale, Victoria L 
Lelieveld, Lindsey T 
Busch-Nentwich, Elisabeth M 

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.

Description

Keywords

Gaucher disease, lysosomal glucosylsphingosine, macrophages, tuberculosis resistance, zebrafish, Animals, Gaucher Disease, Zebrafish, Glucosylceramidase, Mutation, Tuberculosis

Journal Title

Proc Natl Acad Sci U S A

Conference Name

Journal ISSN

0027-8424
1091-6490

Volume Title

120

Publisher

Proceedings of the National Academy of Sciences
Sponsorship
National Institutes of Health (NIH) (7R37A1054503-13)
Wellcome Trust (223103/Z/21/Z)
National Institute for Health and Care Research (IS-BRC-1215-20014)
Medical Research Council (MR/K015338/1)
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