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

Marquet, Sandrine and Bucheton, Bruno and Reymond, Camille and Argiro, Laurent and El-Safi, Sayda Hassan and Kheir, Musa Mohamed and Desvignes, Jean-Pierre and Béroud, Christophe and Mergani, Adil and Hammad, Awad and Dessein, Alain J (2017) Exome Sequencing Identifies Two Variants of the Alkylglycerol Monooxygenase Gene as a Cause of Relapses in Visceral Leishmaniasis in Children, in Sudan. The Journal of infectious diseases, 216 (1). pp. 22-28. ISSN 1537-6613

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Abstract

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.

Item Type: Article
Subjects: R Medicine > RH Biochemistry
Q Science > QR Microbiology
R Medicine > RJ Pediatrics
Divisions: University of Khartoum > Faculty of Medicine, Health and Life Sciences > Department of Medicine
Depositing User: Moneeb Hassan
Date Deposited: 14 Jan 2018 05:09
Last Modified: 14 Jan 2018 05:09
URI: http://search.srh.edu.sd/id/eprint/3841

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