Homozygous DBF4 mutation as a cause of severe congenital neutropenia.
DBF4
DNA replication
facial dysmorphism
genetics
inborn errors of immunity
mutation
neutropenia
perturbed growth
primary immunodeficiency
Journal
The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002
Informations de publication
Date de publication:
Jul 2023
Jul 2023
Historique:
received:
08
09
2022
revised:
23
01
2023
accepted:
16
02
2023
medline:
10
7
2023
pubmed:
26
2
2023
entrez:
25
2
2023
Statut:
ppublish
Résumé
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 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 Hypomorphic DBF4 mutation causes autosomal-recessive severe congenital neutropenia with syndromic features.
Sections du résumé
BACKGROUND
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
OBJECTIVE
We aimed to characterize a patient with severe congenital neutropenia and syndromic features without a genetic diagnosis.
METHODS
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
RESULTS
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
CONCLUSION
CONCLUSIONS
Hypomorphic DBF4 mutation causes autosomal-recessive severe congenital neutropenia with syndromic features.
Identifiants
pubmed: 36841265
pii: S0091-6749(23)00230-0
doi: 10.1016/j.jaci.2023.02.016
pii:
doi:
Substances chimiques
Cell Cycle Proteins
0
Protein Serine-Threonine Kinases
EC 2.7.11.1
Saccharomyces cerevisiae Proteins
0
CDC7 protein, human
EC 2.7.1.-
DBF4 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
266-277Subventions
Organisme : Medical Research Council
ID : MR/T012978/1
Pays : United Kingdom
Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.