Marquet S. auteur aut IRD Bucheton Bruno auteur aut IRD Reymond C. auteur aut IRD Argiro L. auteur aut IRD El-Safi S. H. auteur aut IRD Kheir M. M. auteur aut IRD Desvignes J. P. auteur aut IRD Beroud C. auteur aut IRD Mergani A. auteur aut IRD Hammad A. auteur aut IRD Dessein A. J. auteur aut IRD text journalArticle eng text/pdf born digital access Visceral leishmaniasis (kala-azar, KA) is the most severe form of leishmaniasis, characterized by fever, weight loss, hepatosplenomegaly, and lymphadenopathy. During an outbreak of KA in Babar El Fugara (Sudan), 5.7% of cured patients displayed relapses, with familial clustering in half the cases. We performed whole-exome sequencing on 10 relapsing individuals and 11 controls from 5 nuclear families. Rare homozygous and compound-heterozygous nonsense (c.1213C > T, rs139309795, p.Arg405*) and missense (c.701A > G, rs143439626, p.Lys234Arg) mutations of the alkylglycerol monooxygenase (AGMO) gene were associated with KA relapse in 3 families. Sequencing in additional family members confirmed the segregation of these mutations with relapse and revealed an autosomal dominant mode of transmission. These mutations were detected heterozygous in 2 subjects among 100 unrelated individuals with KA who never relapsed after cure, suggesting incomplete penetrance of AGMO deficiency. AGMO is expressed in hematopoietic cells, and is strongly expressed in the liver. AGMO modulates PAF production by mouse macrophages, suggesting that it may act through the PAF/PAF receptor pathway previously shown to have anti-Leishmania activity. This is the first demonstration that relapses after a first episode of KA are due to differences in human genetic susceptibility and not to modifications of parasite pathogenicity. specialized AGMO exome sequencing genetic variants haploinsufficiency Kala-azar relapse SOUDAN 052 050 216 1 22-28 2017 0022-1899 https://www.documentation.ird.fr/hor/fdi:010070378 10.1093/infdis/jix277 0022-1899 [F B010070378] https://www.documentation.ird.fr/hor/fdi:010070378 https://www.documentation.ird.fr/intranet/publi/2017/08/010070378.pdf Accès réservé (Intranet de l'IRD) IRD - Base Horizon / Pleins textes 2017-09-05 2023-07-11 fdi:010070378 fre