PXD014633

PXD014633 is an original dataset announced via ProteomeXchange.

Title	MKL1 deficiency results in a neutrophil motility defect with impaired actin polymerization and excessive degranulation
Description	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.
HostingRepository	PRIDE
AnnounceDate	2025-09-30
AnnouncementXML	Submission_2025-09-30_01:37:20.543.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Floris van Alphen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2019-07-16 07:33:08	ID requested
⏵ 1	2025-09-30 01:37:21	announced

Sprenkeler EGG, Henriet SSV, Tool ATJ, Kreft IC, van der Bijl I, Aarts CEM, van Houdt M, Verkuijlen PJJH, van Aerde K, Jaspers G, van Heijst A, Koole W, Gardeitchik T, Geissler J, de Boer M, Tol S, Bruggeman CW, van Alphen FPJ, Verhagen HJMP, van den Akker E, Janssen H, van Bruggen R, van den Berg TK, Liem KD, Kuijpers TW, MKL1 deficiency results in a severe neutrophil motility defect due to impaired actin polymerization. Blood, 135(24):2171-2181(2020) [pubmed]

10.1182/blood.2019002633;

submitter keyword: MKL1, Actin poymerization,Neutrophils, SRF, MRTF-A

Prof. Dr. A.B. Meijer,
contact affiliation	Sanquin Research, Department of Molecular and Cellular Hemostasis and Utrecht University
contact email	S.Meijer@sanquin.nl
lab head
Floris van Alphen
contact affiliation	Sanquin Research
contact email	f.vanalphen@sanquin.nl
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD014633
     1. Label: PRIDE project
     2. Name: MKL1 deficiency results in a neutrophil motility defect with impaired actin polymerization and excessive degranulation