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Homozygous DBF4 mutation as a cause for severe congenital neutropenia

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posted on 2023-06-10, 06:35 authored by Mathijs Willemsen, John S Barber, Erika Van Nieuwenhove, Frederik Staels, Margaux Gerbaux, Julika Neumann, Teresa Prezzemolo, Emanuela Pasciuto, Vasiliki Lagou, Nancy Boeckx, Jessica Filtjens, Amber De Visscher, Patrick Matthys, Rik Schrijvers, Thomas Tousseyn, Mark O'DriscollMark O'Driscoll, Giorgia Bucciol, Susan Schlenner, Isabelle Meyts, Stephanie Humblet-Baron, Adrian Liston
Background Severe congenital neutropenia presents with recurrent infections early in life due to 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, co-immunoprecipitation, 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 variant allele 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 WT DBF4 into patient CD34+ cells rescued the promyelocyte differentiation arrest. Conclusion Hypomorphic DBF4 mutation causes autosomal recessive severe congenital neutropenia with syndromic features.


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Journal of Allergy and Clinical Immunology





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aS0091 1-12

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United States

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  • Sussex Centre for Genome Damage Stability Publications

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