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Homozygous DBF4 mutation as a cause of severe congenital neutropenia

par Willemsen, Mathijs;Barber, John J.S.;Van Nieuwenhove, Erika;Staels, Frederik;Gerbaux, Margaux ;Neumann, Julika;Prezzemolo, Teresa;Pasciuto, Emanuela;Lagou, Vasiliki;Boeckx, Nancy;Filtjens, Jessica;De Visscher, Amber;Matthys, Patrick;Schrijvers, Rik;Tousseyn, Thomas;O'Driscoll, Mark;Bucciol, Giorgia;Schlenner, Susan;Meyts, Isabelle;Humblet-Baron, Stéphanie;Liston, Adrian
Référence Journal of allergy and clinical immunology, 152, 1, page (266-277)
Publication Publié, 2023-07

Article révisé par les pairs

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Résumé :

Background: Severe congenital neutropenia presents with recurrent infections early in life as a result of arrested granulopoiesis. Multiple genetic defects are known to block granulocyte differentiation; however, a genetic cause remains unknown in approximately 40% of cases. Objective: We aimed to characterize a patient with severe congenital neutropenia and syndromic features without a genetic diagnosis. Methods: Whole exome sequencing results were validated using flow cytometry, Western blotting, coimmunoprecipitation, quantitative PCR, cell cycle and proliferation analysis of lymphocytes and fibroblasts and granulocytic differentiation of primary CD34+ and HL-60 cells. Results: We identified a homozygous missense mutation in DBF4 in a patient with mild extra-uterine growth retardation, facial dysmorphism and severe congenital neutropenia. DBF4 is the regulatory subunit of the CDC7 kinase, together known as DBF4-dependent kinase (DDK), the complex essential for DNA replication initiation. The DBF4 variant demonstrated impaired ability to bind CDC7, resulting in decreased DDK-mediated phosphorylation, defective S-phase entry and progression and impaired differentiation of granulocytes associated with activation of the p53-p21 pathway. The introduction of wild-type DBF4 into patient CD34+ cells rescued the promyelocyte differentiation arrest. Conclusion: Hypomorphic DBF4 mutation causes autosomal-recessive severe congenital neutropenia with syndromic features.