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Defective neutrophil development and specific granule deficiency caused by a homozygous splice-site mutation in SMARCD2

Lookup NU author(s): Dr Ina Schim van der LoeffORCiD, Dr Mario Abinun, Angela Grainger, Dr Karin Engelhardt, Dr Sophie Hambleton



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2020 The Authors. Background: SMARCD2 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily D, member 2) has recently been shown to have a critical role in granulopoiesis in humans, mice, and zebrafish. Our patient presented with delayed cord separation, failure to thrive, and sepsis. Retrospective whole-exome sequencing confirmed a homozygous splice-site mutation in SMARCD2. Objective: We sought to provide the second description of human SMARCD2 deficiency and the first functional analysis of human primary SMARCD2-deficient cells. Methods: Heparinized venous blood and bone marrow were collected from the patient after obtaining informed consent. Patient leukocytes and CD34+ cells were then isolated, phenotyped, and assessed functionally. Results: Circulating neutrophils appeared phenotypically immature, lacking multilobed nuclei, and neutrophil granules lacked lactoferrin but showed normal levels of myeloperoxidase. Neutrophil oxidative burst was preserved in response to phorbol 12-myristate 13-acetate. Patient bone marrow–derived neutrophils and white blood cells showed a severely impaired chemotactic response. Furthermore, white blood cells showed defective in vitro killing of Staphylococcus aureus, consistent with a specific granule deficiency. Finally, patient bone marrow–derived CD34+ cells showed markedly impaired in vitro expansion and differentiation toward the neutrophil lineage. Before her molecular diagnosis, our patient underwent hematopoietic stem cell transplantation and is well 8 years later. Conclusions: This report highlights an important role for SMARCD2 in human myelopoiesis and the curative effect of hematopoietic stem cell transplantation for the hematopoietic features of SMARCD2 deficiency.

Publication metadata

Author(s): Schim van der Loeff I, Sprenkeler EGG, Tool ATJ, Abinun M, Grainger A, Engelhardt KR, van Houdt M, Janssen H, Kuijpers TW, Hambleton S

Publication type: Article

Publication status: Published

Journal: Journal of Allergy and Clinical Immunology

Year: 2021

Volume: 147

Issue: 6

Pages: 2381-2385.e2

Print publication date: 01/06/2021

Online publication date: 03/12/2020

Acceptance date: 05/11/2020

Date deposited: 05/10/2023

ISSN (print): 0091-6749

ISSN (electronic): 1097-6825

Publisher: Mosby Inc.


DOI: 10.1016/j.jaci.2020.11.025

PubMed id: 33279574


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