New px1 Gene Mutation Drives Rapid Rise of Drug-Resistant Malaria in Uganda
Researchers discovered a cluster of mutations called PIN in the px1 gene that makes malaria parasites less sensitive to lumefantrine and other drugs, spreading swiftly across northern and eastern Uganda.
A study led by Brown University researchers, published in Nature Medicine, reports that a previously overlooked gene, px1, harbors a mutation cluster named PIN—three amino-acid substitutions and two deletions—that is linked to reduced susceptibility of malaria parasites to lumefantrine and several other antimalarials. Whole-genome sequencing of 157 Ugandan samples from 2016-2024 revealed the mutation first emerged in a 2008 specimen and expanded rapidly, reaching 84% of parasites in northern Uganda and 55% in the east by 2024.
Experiments comparing PIN-positive and PIN-negative parasites demonstrated diminished drug response in the former, while parasites engineered without the px1 gene were more drug-sensitive. The mutation did not affect artemisinin resistance, which remains associated with Kelch13 variants. Historical data show PIN was rare before 2015, with only five detections in neighboring Congo and Kenya, and absent in 2010 Ugandan samples. Researchers stress the need to add PIN to molecular surveillance and to develop predictive tools and new treatments to safeguard malaria control.
Why it matters
The spread of a mutation that weakens key malaria drugs threatens treatment effectiveness in sub-Saharan Africa.
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