MKL1 deficiency results in a severe neutrophil motility defect due to impaired actin polymerization.

Blood
Evelien G G SprenkelerTaco W Kuijpers

Abstract

Megakaryoblastic leukemia 1 (MKL1) promotes the regulation of essential cell processes, including actin cytoskeletal dynamics, by coactivating serum response factor. Recently, the first human with MKL1 deficiency, leading to a novel primary immunodeficiency, was identified. We report a second family with 2 siblings with a homozygous frameshift mutation in MKL1. The index case died as an infant from progressive and severe pneumonia caused by Pseudomonas aeruginosa and poor wound healing. The younger sibling was preemptively transplanted shortly after birth. The immunodeficiency was marked by a pronounced actin polymerization defect and a strongly reduced motility and chemotactic response by MKL1-deficient neutrophils. In addition to the lack of MKL1, subsequent proteomic and transcriptomic analyses of patient neutrophils revealed actin and several actin-related proteins to be downregulated, confirming a role for MKL1 as a transcriptional coregulator. Degranulation was enhanced upon suboptimal neutrophil activation, whereas production of reactive oxygen species was normal. Neutrophil adhesion was intact but without proper spreading. The latter could explain the observed failure in firm adherence and transendothelial migration und...Continue Reading

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Citations

Jan 26, 2021·Frontiers in Immunology·Riccardo PapaMarco Gattorno
Mar 9, 2021·Frontiers in Immunology·Panagiota BoutiTaco W Kuijpers
Mar 17, 2021·The Journal of Biological Chemistry·Fiona ReedDiane S Krause
Dec 7, 2020·The Journal of Allergy and Clinical Immunology·Ina Schim van der LoeffSophie Hambleton
Aug 24, 2021·Frontiers in Cell and Developmental Biology·Julien RecordLisa S Westerberg

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