TY - JOUR
T1 - Defective neutrophil development and specific granule deficiency caused by a homozygous splice-site mutation in SMARCD2
AU - Schim van der Loeff, Ina
AU - Sprenkeler, Evelien G. G.
AU - Tool, Anton T. J.
AU - Abinun, Mario
AU - Grainger, Angela
AU - Engelhardt, Karin R.
AU - van Houdt, Michel
AU - Janssen, Hans
AU - Kuijpers, Taco W.
AU - Hambleton, Sophie
N1 - Funding Information: Work in the Primary Immunodeficiency Group was supported by the Medical Research Council, the Sir Jules Thorn Trust (grant no. 12/JTA) and Wellcome (grant no. 207556_Z_17_Z). E.G.G.S. and T.W.K. were funded in part by the European Union's Horizon 2020 research and innovation program (grant agreement no. 668303), and T.W.K. was funded in part by the Center of Immunodeficiencies Amsterdam (grant no. CIDA-2015). I.S.v.d.L. is supported by an academic clinical fellowship from the National Institute for Health Research. Funding Information: Work in the Primary Immunodeficiency Group was supported by the Medical Research Council , the Sir Jules Thorn Trust (grant no. 12/JTA ) and Wellcome (grant no. 207556_Z_17_Z ). E.G.G.S. and T.W.K. were funded in part by the European Union’s Horizon 2020 research and innovation program (grant agreement no. 668303 ), and T.W.K. was funded in part by the Center of Immunodeficiencies Amsterdam (grant no. CIDA-2015 ). I.S.v.d.L. is supported by an academic clinical fellowship from the National Institute for Health Research . Publisher Copyright: © 2020 The Authors Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/6
Y1 - 2021/6
N2 - 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.
AB - 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.
KW - CEBPε
KW - Splice-site mutation
KW - chemotaxis
KW - inborn error of immunity
KW - lactoferrin
KW - neutrophil-specific granule deficiency
KW - phagocyte disorder
UR - http://www.scopus.com/inward/record.url?scp=85098544962&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.jaci.2020.11.025
DO - https://doi.org/10.1016/j.jaci.2020.11.025
M3 - Article
C2 - 33279574
SN - 0091-6749
VL - 147
SP - 2381-2385.e2
JO - Journal of allergy and clinical immunology
JF - Journal of allergy and clinical immunology
IS - 6
ER -