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Study Points to Tuberculosis Protection by Gaucher Disease Mutation

In the Proceedings of the National Academy of Sciences, an international team led by investigators at the University of Cambridge and the MRC Laboratory of Molecular Biology describe lower-than-usual susceptibility to the tuberculosis (TB) pathogen Mycobacterium tuberculosis in mutant zebrafish models carrying GBA1, glucocerebrosidase enzyme-coding gene, mutations. These mutations are involved in the autosomal recessive condition Gaucher disease — marked by glucosylceramide and glucosylsphingosine lipid accumulation in macrophage lysosomes. In their GBA1-mutant zebrafish models, the researchers found that homozygous mutation carriers had reduced TB susceptibility, particularly when it came to a GBA1 mutation known as N370S that has been implicated in Gaucher disease in individuals of Ashkenazi Jewish ancestry. "[W]e find that the mutation GBA1 N370S, predominant among Ashkenazi Jews, increases resistance to tuberculosis through the microbicidal activity of glucosylsphingosine in macrophage lysosomes," they report, noting that these and other results "provide biological plausibility for [N370S] 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."