Exome Sequencing Identifies Two Variants of the Alkylglycerol Monooxygenase Gene as a Cause of Relapses in Visceral Leishmaniasis in Children, in Sudan.

Autor:	Marquet S; INSERM UMR906, GIMP, Labex ParaFrap, Aix-Marseille University, Marseille., Bucheton B; INSERM UMR906, GIMP, Labex ParaFrap, Aix-Marseille University, Marseille.; Institut de Recherche pour le Développement, Unité Mixte de Recherche IRD-CIRAD 177, Campus International de Baillarguet, Montpellier, France., Reymond C; INSERM UMR906, GIMP, Labex ParaFrap, Aix-Marseille University, Marseille., Argiro L; INSERM UMR906, GIMP, Labex ParaFrap, Aix-Marseille University, Marseille., El-Safi SH; Department of Microbiology and Parasitology, Faculty of Medicine, University of Khartoum, Khartoum, Sudan., Kheir MM; Department of Microbiology and Parasitology, Faculty of Medicine, University of Khartoum, Khartoum, Sudan., Desvignes JP; INSERM UMR910, GMGF, Aix-Marseille University., Béroud C; INSERM UMR910, GMGF, Aix-Marseille University.; AP-HM, Département de Génétique Médicale, Hôpital Timone Enfants, Marseille, France., Mergani A; College of Applied Medical Sciences, Taif University, Turabah, Saudi Arabia., Hammad A; Department of Microbiology and Parasitology, Faculty of Medicine, University of Khartoum, Khartoum, Sudan., Dessein AJ; INSERM UMR906, GIMP, Labex ParaFrap, Aix-Marseille University, Marseille.
Jazyk:	angličtina
Zdroj:	The Journal of infectious diseases [J Infect Dis] 2017 Jul 01; Vol. 216 (1), pp. 22-28.
DOI:	10.1093/infdis/jix277
Abstrakt:	Background: 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. Methods: We performed whole-exome sequencing on 10 relapsing individuals and 11 controls from 5 nuclear families. Results: 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. Conclusions: 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. (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu