title: Immunodeficiency and severe susceptibility to bacterial infection associated with a loss-of-function homozygous mutation of MKL1.
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.
authors.affiliation: University College London Institute of Child Health, London, United Kingdom;
authors.forename: Julien
authors.identifier: http://orcid.org/0000-0003-1138-2916
authors.initials: J
authors.lastname: Record
authors.affiliation: University College London Institute of Child Health, London, United Kingdom;
authors.forename: Dessislava
authors.initials: D
authors.lastname: Malinova
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, United Kingdom;
authors.forename: Helen L
authors.initials: HL
authors.lastname: Zenner
authors.affiliation: University College London Genetics Institute, University College London, London, United Kingdom;
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.affiliation: University College London Institute of Child Health, London, United Kingdom;
authors.forename: Karolin
authors.initials: K
authors.lastname: Nowak
authors.affiliation: University College London Institute of Child Health, London, United Kingdom;
authors.forename: Farhatullah
authors.initials: F
authors.lastname: Syed
authors.affiliation: University College London Institute of Child Health, London, United Kingdom;
authors.forename: Gerben
authors.initials: G
authors.lastname: Bouma
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, United Kingdom;
authors.forename: James
authors.initials: J
authors.lastname: Curtis
authors.affiliation: Great Ormond Street Hospital for Children National Health Service (NHS) Foundation Trust, London, United Kingdom;
authors.forename: Kimberly
authors.initials: K
authors.lastname: Gilmour
authors.affiliation: Great Ormond Street Hospital for Children National Health Service (NHS) Foundation Trust, London, United Kingdom;
authors.forename: Catherine
authors.initials: C
authors.lastname: Cale
authors.affiliation: Birmingham Heartland Hospital, Birmingham, United Kingdom;
authors.forename: Scott
authors.initials: S
authors.lastname: Hackett
authors.affiliation: London Centre for Nanotechnology, Department of Cell and Developmental Biology, University College London, London, United Kingdom;
authors.forename: Guillaume
authors.initials: G
authors.lastname: Charras
authors.affiliation: University College London Institute of Child Health, London, United Kingdom;
authors.forename: Dale
authors.initials: D
authors.lastname: Moulding
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, United Kingdom;
authors.forename: Sergey
authors.initials: S
authors.lastname: Nejentsev
authors.affiliation: University College London Institute of Child Health, London, United Kingdom; Great Ormond Street Hospital for Children National Health Service (NHS) Foundation Trust, London, United Kingdom;
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
authors.affiliation: Department of Immunology, Royal Free London NHS Foundation Trust, London, United Kingdom; and University College London Institute of Immunity and Transplantation, London, United Kingdom.
authors.forename: Siobhan O
authors.initials: SO
authors.lastname: Burns
mesh_terms: D000199:Actins / Q000378:metabolism / Q000648:ultrastructure; D002460:Cell Line; D002465:Cell Movement; D002478:Cells, Cultured; D018389:Codon, Nonsense; D003599:Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000150:complications / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D011549:Pseudomonas / Q000302:isolation & purification; D011552:Pseudomonas Infections / Q000150:complications / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics*
chemical_list: D000199:Actins; D018389:Codon, Nonsense; C431575:MRTFA protein, human; D015534:Trans-Activators