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Immunodeficiency and severe susceptibility to bacterial infection associated with a loss-of-function homozygous mutation of MKL1.
Blood. 2015 Jul 29;
Authors: Record J, Malinova D, Zenner HL, Plagnol V, Nowak K, Syed F, Bouma G, Curtis J, Gilmour K, Cale C, Hackett S, Charras G, Moulding D, Nejentsev S, Thrasher AJ, Burns SO
Abstract
Megakaryoblastic Leukemia 1 (MKL1), also known as MAL or MRTF-A, is a co-activator of serum response factor (SRF), regulating transcription of actin and actin cytoskeleton-related genes. MKL1 is known to be important for megakaryocyte differentiation and function in mice but its role in immune cells is unexplored. Here we report a patient with a homozygous nonsense mutation in the MKL1 gene resulting in immunodeficiency characterised predominantly by susceptibility to severe bacterial infection. We show that loss of MKL1 protein expression causes a dramatic loss of F-actin content in lymphoid and myeloid lineage immune cells and widespread cytoskeletal dysfunction. MKL1-deficient neutrophils displayed reduced phagocytosis and almost complete abrogation of migration in vitro. Similarly, primary dendriritic cells were unable to spread normally or to form podosomes. Silencing of MKL1 in myeloid cell lines revealed that F-actin assembly was abrogated through reduction of G-actin levels and disturbed expression of multiple actin-regulating genes. Impaired migration of these cells was associated with failure of uropod retraction likely due to altered contractility and adhesion, evidenced by reduced expression of the MYL9 component of myosin II complex and over expression of CD11b integrin. Together, our results show that MKL1 is a non-redundant regulator of cytoskeleton-associated functions in immune cells and fibroblasts and that its depletion underlies a novel human primary immunodeficiency.
PMID: 26224645 [PubMed – as supplied by publisher]
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