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

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....

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Autores principales: Schim van der Loeff, Ina, Sprenkeler, Evelien G.G., Tool, Anton T.J., Abinun, Mario, Grainger, Angela, Engelhardt, Karin R., van Houdt, Michel, Janssen, Hans, Kuijpers, Taco W., Hambleton, Sophie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Mosby 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168953/
https://www.ncbi.nlm.nih.gov/pubmed/33279574
http://dx.doi.org/10.1016/j.jaci.2020.11.025
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author Schim van der Loeff, Ina
Sprenkeler, Evelien G.G.
Tool, Anton T.J.
Abinun, Mario
Grainger, Angela
Engelhardt, Karin R.
van Houdt, Michel
Janssen, Hans
Kuijpers, Taco W.
Hambleton, Sophie
author_facet Schim van der Loeff, Ina
Sprenkeler, Evelien G.G.
Tool, Anton T.J.
Abinun, Mario
Grainger, Angela
Engelhardt, Karin R.
van Houdt, Michel
Janssen, Hans
Kuijpers, Taco W.
Hambleton, Sophie
author_sort Schim van der Loeff, Ina
collection PubMed
description 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.
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spelling pubmed-81689532021-06-05 Defective neutrophil development and specific granule deficiency caused by a homozygous splice-site mutation in SMARCD2 Schim van der Loeff, Ina Sprenkeler, Evelien G.G. Tool, Anton T.J. Abinun, Mario Grainger, Angela Engelhardt, Karin R. van Houdt, Michel Janssen, Hans Kuijpers, Taco W. Hambleton, Sophie J Allergy Clin Immunol Brief Report 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. Mosby 2021-06 /pmc/articles/PMC8168953/ /pubmed/33279574 http://dx.doi.org/10.1016/j.jaci.2020.11.025 Text en © 2020 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Brief Report
Schim van der Loeff, Ina
Sprenkeler, Evelien G.G.
Tool, Anton T.J.
Abinun, Mario
Grainger, Angela
Engelhardt, Karin R.
van Houdt, Michel
Janssen, Hans
Kuijpers, Taco W.
Hambleton, Sophie
Defective neutrophil development and specific granule deficiency caused by a homozygous splice-site mutation in SMARCD2
title Defective neutrophil development and specific granule deficiency caused by a homozygous splice-site mutation in SMARCD2
title_full Defective neutrophil development and specific granule deficiency caused by a homozygous splice-site mutation in SMARCD2
title_fullStr Defective neutrophil development and specific granule deficiency caused by a homozygous splice-site mutation in SMARCD2
title_full_unstemmed Defective neutrophil development and specific granule deficiency caused by a homozygous splice-site mutation in SMARCD2
title_short Defective neutrophil development and specific granule deficiency caused by a homozygous splice-site mutation in SMARCD2
title_sort defective neutrophil development and specific granule deficiency caused by a homozygous splice-site mutation in smarcd2
topic Brief Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168953/
https://www.ncbi.nlm.nih.gov/pubmed/33279574
http://dx.doi.org/10.1016/j.jaci.2020.11.025
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