Sandrine Marquet1, Bruno Bucheton1,2, Camille Reymond1, Laurent Argiro1, Sayda Hassan El-Safi3, Musa Mohamed Kheir3, Jean-Pierre Desvignes4, Christophe Béroud4,5, Adil Mergani6, Awad Hammad3, Alain J Dessein1. 1. INSERM UMR906, GIMP, Labex ParaFrap, Aix-Marseille University, Marseille. 2. Institut de Recherche pour le Développement, Unité Mixte de Recherche IRD-CIRAD 177, Campus International de Baillarguet, Montpellier, France. 3. Department of Microbiology and Parasitology, Faculty of Medicine, University of Khartoum, Khartoum, Sudan. 4. INSERM UMR910, GMGF, Aix-Marseille University. 5. AP-HM, Département de Génétique Médicale, Hôpital Timone Enfants, Marseille, France. 6. College of Applied Medical Sciences, Taif University, Turabah, Saudi Arabia.
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.
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.
Authors: Sabrina Sailer; Katharina Lackner; Mia L Pras-Raves; Eric J M Wever; Jan B van Klinken; Adriaan D Dane; Stephan Geley; Jakob Koch; Georg Golderer; Gabriele Werner-Felmayer; Markus A Keller; Werner Zwerschke; Frédéric M Vaz; Ernst R Werner; Katrin Watschinger Journal: J Lipid Res Date: 2022-05-07 Impact factor: 6.676
Authors: Volkan Okur; Katrin Watschinger; Dmitriy Niyazov; Julie McCarrier; Donald Basel; Martin Hermann; Ernst R Werner; Wendy K Chung Journal: Hum Genet Date: 2019-09-25 Impact factor: 5.881
Authors: Sabrina Sailer; Stefan Coassin; Ernst R Werner; Katrin Watschinger; Katharina Lackner; Caroline Fischer; Eileen McNeill; Gertraud Streiter; Christian Kremser; Manuel Maglione; Catherine M Green; Daniela Moralli; Alexander R Moschen; Markus A Keller; Georg Golderer; Gabriele Werner-Felmayer; Irmgard Tegeder; Keith M Channon; Benjamin Davies Journal: Cell Biosci Date: 2021-03-16 Impact factor: 9.584
Authors: Katrin Watschinger; Markus A Keller; Georg Golderer; Stefan Coassin; Johannes Zschocke; Ernst R Werner Journal: J Infect Dis Date: 2018-05-05 Impact factor: 7.759