Project description:Accurate and efficient DNA synthesis is an essential function of replicating cells. Mutations in replisome components lead to a number of syndromic diseases including immunodeficiencies. Dumbbell former 4 (DBF4) is the regulatory subunit of the DBF4-dependent kinase (DDK) which is essential for the activation of replication origins. We here studied a patient with severe congenital neutropenia (SCN) and syndromic features without a genetic diagnosis. We identified a private homozygous mutation in DBF4 (CADD 25.8 with a DBF4-specific MSC of 3.13) in a patient with SCN. The DBF4 mutant is normally expressed in stimulated PBMCs and dermal fibroblasts, but has a decreased CDC7-binding capacity in overexpression assays. DDK-specific phosphorylation of MCM2 was decreased in stimulated PBMCs with accumulation of CDK inhibitor p21, a G0 cell cycle arrest and impaired proliferation. Serum-starved fibroblasts showed a similar cell cycle phenotype but no p21 accumulation and normal MCM2 phosphorylation. In vitro differentiation of primary CD34+ cells recapitulated the SCN phenotype observed in vivo and was associated with a 4-fold increase in p21 gene expression. Single cell RNA sequencing of whole bone marrow revealed upregulation of p53 targets and activation of the PERK pathway of the unfolded protein response. Autosomal recessive functional DBF4 deficiency causes SCN with syndromic features.

2022-06-10 | GSE160517 | GEO

Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic <i>IKBKG</i>/NEMO mutations.

Project description: Not available

| S-EPMC5609334 | biostudies-literature

Dendritic cells from humans with hypomorphic mutations in IKBKG/NEMO have impaired mitogen-activated protein kinase activity.

Project description: Not available

| S-EPMC3134100 | biostudies-literature

A novel hypomorphic mutation in <i>IL2RG</i> associated with severe interstitial lung disease.

Project description: Not available

| S-EPMC12396425 | biostudies-literature

Incontinentia pigmenti in a newborn with NEMO mutation.

Project description: Not available