Exome Sequencing Identifies Two Variants of the Alkylglycerol Monooxygenase Gene as a Cause of Relapses in Visceral Leishmaniasis in Children, in Sudan - Aix-Marseille Université Accéder directement au contenu
Article Dans Une Revue Journal of Infectious Diseases Année : 2017

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

Sandrine Marquet
Bruno Bucheton
  • Fonction : Auteur
Camille Reymond
  • Fonction : Auteur
Laurent Argiro
  • Fonction : Auteur
Sayda Hassan El-Safi
  • Fonction : Auteur
Musa Mohamed Kheir
  • Fonction : Auteur
Adil Mergani
  • Fonction : Auteur
Awad Hammad
  • Fonction : Auteur
Alain J. Dessein
  • Fonction : Auteur

Résumé

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.
Fichier principal
Vignette du fichier
J. Infect. Dis. 2017 Marquet.pdf (763.56 Ko) Télécharger le fichier
Origine : Fichiers produits par l'(les) auteur(s)
Loading...

Dates et versions

hal-01741722 , version 1 (30-04-2018)

Identifiants

Citer

Sandrine Marquet, Bruno Bucheton, Camille Reymond, Laurent Argiro, Sayda Hassan El-Safi, et al.. Exome Sequencing Identifies Two Variants of the Alkylglycerol Monooxygenase Gene as a Cause of Relapses in Visceral Leishmaniasis in Children, in Sudan. Journal of Infectious Diseases, 2017, 216 (1), pp.22-28. ⟨10.1093/infdis/jix277⟩. ⟨hal-01741722⟩

Collections

CNRS UNIV-AMU MMG
90 Consultations
77 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More