Erschienen in:
05.03.2019 | Original Article
Human DOCK2 Deficiency: Report of a Novel Mutation and Evidence for Neutrophil Dysfunction
verfasst von:
Leen Moens, Mieke Gouwy, Barbara Bosch, Oleksandr Pastukhov, Alejandro Nieto-Patlàn, Ulrich Siler, Giorgia Bucciol, Djalila Mekahli, François Vermeulen, Lars Desmet, Sophie Maebe, Helena Flipts, Anniek Corveleyn, Despina Moshous, Pierre Philippet, Stuart G. Tangye, Bertrand Boisson, Jean-Laurent Casanova, Benoit Florkin, Sofie Struyf, Janine Reichenbach, Jacinta Bustamante, Luigi D. Notarangelo, Isabelle Meyts
Erschienen in:
Journal of Clinical Immunology
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Ausgabe 3/2019
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Abstract
DOCK2 is a guanine-nucleotide-exchange factor for Rac proteins. Activated Rac serves various cellular functions including the reorganization of the actin cytoskeleton in lymphocytes and neutrophils and production of reactive oxygen species in neutrophils. Since 2015, six unrelated patients with combined immunodeficiency and early-onset severe viral infections caused by bi-allelic loss-of-function mutations in DOCK2 have been described. Until now, the function of phagocytes, specifically neutrophils, has not been assessed in human DOCK2 deficiency. Here, we describe a new kindred with four affected siblings harboring a homozygous splice-site mutation (c.2704-2 A > C) in DOCK2. The mutation results in alternative splicing and a complete loss of DOCK2 protein expression. The patients presented with leaky severe combined immunodeficiency or Omenn syndrome. The novel mutation affects EBV-B cell migration and results in NK cell dysfunction similar to previous observations. Moreover, both cytoskeletal rearrangement and reactive oxygen species production are partially impaired in DOCK2-deficient neutrophils.