Homozygous DBF4 mutation as a cause of severe congenital neutropenia

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. We aimed to characterize a patient w...

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Published inJournal of allergy and clinical immunology Vol. 152; no. 1; pp. 266 - 277
Main Authors Willemsen, Mathijs, Barber, John S., Nieuwenhove, Erika Van, 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, Stephanie, Liston, Adrian
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 01.07.2023
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Summary: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. We aimed to characterize a patient with severe congenital neutropenia and syndromic features without a genetic diagnosis. 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. 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. Hypomorphic DBF4 mutation causes autosomal-recessive severe congenital neutropenia with syndromic features.
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ISSN:0091-6749
1097-6825
DOI:10.1016/j.jaci.2023.02.016