Dataset Information

MKL1 deficiency results in a neutrophil motility defect with impaired actin polymerization and excessive degranulation

ABSTRACT: Megakaryoblastic leukemia 1 (MKL1) promotes the regulation of essential cell processes, including actin cytoskeletal dynamics by co-activating serum response factor. Recently, the first human case with MKL1 deficiency has been identified, leading to a novel primary immunodeficiency. We report a second family with two siblings with a homozygous frameshift mutation in MKL1. The index case deceased as an infant from progressive and severe pneumonia by Pseudomonas aeruginosa and poor wound healing. The younger sib was preemptively transplanted shortly after birth. The immunodeficiency was marked by a pronounced actin polymerization defect and a strongly reduced motility and chemotactic response of MKL1-deficient neutrophils. Apart from the lack of MKL1, subsequent proteomic and transcriptomic analyses of patient neutrophils revealed G-actin and several actin-related proteins to be downregulated, confirming a role of MKL1 as transcriptional co-regulator. Degranulation was enhanced upon suboptimal neutrophil activation, while production of reactive oxygen species (ROS) was normal. Neutrophil adhesion was intact but without proper spreading. The latter could explain the observed failure in firm adherence and transendothelial migration under flow conditions. No apparent phagocytosis- and bacterial killing defect was found. Also monocyte-derived macrophages showed intact phagocytosis; lymphocyte counts and proliferative capacity were normal. Non-hematopoietic primary patient fibroblasts demonstrated defective differentiation into myofibroblasts but normal migration and filamentous actin (F-actin) content, most likely due to compensatory mechanisms of MKL2 which is not expressed in leukocytes. Our findings extend current insight into the severe immune dysfunction in MKL1 deficiency, with cytoskeletal dysfunction and defective extravasation of neutrophils as most prominent features.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Polymorphonuclear Neutrophil, Neutrophil

DISEASE(S): Primary Immunodeficiency Disease

SUBMITTER: Floris van Alphen

LAB HEAD: Prof. Dr. A.B. Meijer,

PROVIDER: PXD014633 | Pride | 2025-09-30

REPOSITORIES: Pride

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

Sprenkeler Evelien G G EGG Henriet Stefanie S V SSV Tool Anton T J ATJ Kreft Iris C IC van der Bijl Ivo I Aarts Cathelijn E M CEM van Houdt Michel M Verkuijlen Paul J J H PJJH van Aerde Koen K Jaspers Gerald G van Heijst Arno A Koole Wouter W Gardeitchik Thatjana T Geissler Judy J de Boer Martin M Tol Simon S Bruggeman Christine W CW van Alphen Floris P J FPJ Verhagen Han J M P HJMP van den Akker Emile E Janssen Hans H van Bruggen Robin R van den Berg Timo K TK Liem Kian D KD Kuijpers Taco W TW

Blood 20200601 24

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 youn ...[more]

PMID: 32128589

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