Immunodeficiency and severe susceptibility to bacterial infection associated with a loss-of-function homozygous mutation of MKL1

Julien Record, Dessislava Malinova, Helen L Zenner, Vincent Plagnol, Karolin Nowak, Farhatullah Syed, Gerben Bouma, James Curtis, Kimberly Gilmour, Catherine Cale, Scott Hackett, Guillaume Charras, Dale Moulding, Sergey Nejentsev, Adrian J Thrasher, Siobhan O Burns

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Megakaryoblastic leukemia 1 (MKL1), also known as MAL or myocardin-related transcription factor A (MRTF-A), is a coactivator of serum response factor, which regulates 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 characterized predominantly by susceptibility to severe bacterial infection. We show that loss of MKL1 protein expression causes a dramatic loss of filamentous actin (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 dendritic 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 globular actin (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 myosin light chain 9 (MYL9) component of myosin II complex and overexpression of CD11b integrin. Together, our results show that MKL1 is a nonredundant regulator of cytoskeleton-associated functions in immune cells and fibroblasts and that its depletion underlies a novel human primary immunodeficiency.

Original languageEnglish
Pages (from-to)1527-35
Number of pages9
JournalBlood
Volume126
Issue number13
DOIs
Publication statusPublished - 24 Sep 2015

Cite this

Record, J., Malinova, D., Zenner, H. L., Plagnol, V., Nowak, K., Syed, F., ... Burns, S. O. (2015). Immunodeficiency and severe susceptibility to bacterial infection associated with a loss-of-function homozygous mutation of MKL1. Blood, 126(13), 1527-35. https://doi.org/10.1182/blood-2014-12-611012