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Defective SEC61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia

ABSTRACT: Defective SEC61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia

PROVIDER: PRJNA565728 | ENA |

REPOSITORIES: ENA

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Defective SEC61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia

Project description:The molecular cause of severe congenital neutropenia (SCN) is unknown in 30-50% of patients. SEC61A1 encodes the α subunit of the heterotrimeric SEC61 complex, which governs endoplasmic reticulum (ER) signal peptide-dependent protein transport and passive calcium leakage. Recently, autosomal dominant mutations in SEC61A1 were reported to be pathogenic in common variable immunodeficiency (CVID) and glomerulocystic kidney disease. However the full spectrum of clinical manifestations in SEC61A1 mutations is yet to be explored. We investigated a SCN patient, the only child of healthy non-consanguineous Belgian parents. We identified a de novo private missense mutation in SEC61A1 (c.A275G;p.Q92R; CADD 24.5; msc 6.099) in the patient. The mutation results in diminished expression of the protein in PBMC and fibroblasts, and an increase in calcium leakage from the ER. In vitro differentiation of CD34+ cells recapitulated the patient’s clinical arrest in granulopoiesis. The impact of Q92R-SEC61α1 on neutrophil maturation was validated using HL-60 cells, where transduction reduced differentiation into CD11b+CD16+ cells. A potential mechanism for this defect is the uncontrolled initiation of the unfolded protein stress response (UPR), with single-cell analysis of primary bone-marrow revealing perturbed UPR in myeloid precursors, and in vitro differentiation of primary CD34+ cells into neutrophils revealing upregulation of the pro-apoptotic CHOP and BiP UPR-response genes. Together, these results support specific autosomal dominant mutations in SEC61A1 causing SCN through dysregulation of the UPR.

2020-04-09 | GSE137496 | GEO

Defective Sec61?1 underlies a novel cause of autosomal dominant severe congenital neutropenia.

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Neutrophil granulocyte proteomes of patients with congenital neutropenia

Project description:Proteome profiles of neutrophil granulocytes from patients with severe congenital neutropenia of the genotypes SRP54, SRP19, SRPRA, ELANE, and HAX1

2022-08-09 | PXD035913 | iProX

Severe congenital neutropenia with syndromic features in a patient with homozygous hypomorphic DBF4 mutation

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.

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Connexin46 mutations in autosomal dominant congenital cataract.

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SPP2 Mutations Cause Autosomal Dominant Retinitis Pigmentosa.

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