The following is a summary of “Homozygous DBF4 mutation as a cause of severe congenital neutropenia,” published in the JULY 2023 issue of Allergy (& Immunology) by Willemsen, et al.
For a study, researchers sought to characterize a patient with severe congenital neutropenia and syndromic features, where the genetic cause remained unknown. Using a variety of molecular and cellular assays, including 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, whole exome sequencing was carried out. The results were then validated.
The patient, who had facial dysmorphism, severe congenital neutropenia, and mild extra-uterine growth retardation, had a homozygous missense mutation in DBF4. For DNA replication to begin, the DBF4-dependent kinase (DDK) complex, which is composed of the regulatory component DBF4 and the CDC7 kinase, was required. The identified DBF4 variant showed an impaired ability to bind CDC7, leading to decreased DDK-mediated phosphorylation, defective S-phase entry and progression, and impaired granulocytic differentiation, accompanied by activation of the p53-p21 pathway. Introduction of wild-type DBF4 into patient CD34+ cells rescued the promyelocyte differentiation arrest.
A hypomorphic mutation in DBF4 was found to be the cause of autosomal-recessive severe congenital neutropenia with syndromic features. The study provided new insights into the genetic basis of severe congenital neutropenia and its association with syndromic features.
Source: jacionline.org/article/S0091-6749(23)00230-0/fulltext