Loss of ARHGEF1 causes a human primary antibody deficiency

• Published in: The Journal of clinical investigation Vol. 129; no. 3; pp. 1047 - 1060
• Main Authors: Bouafia, Amine, Lofek, Sébastien, Bruneau, Julie, Chentout, Loïc, Lamrini, Hicham, Trinquand, Amélie, Deau, Marie-Céline, Heurtier, Lucie, Meignin, Véronique, Picard, Capucine, Macintyre, Elizabeth, Alibeu, Olivier, Bras, Marc, Molina, Thierry Jo, Cavazzana, Marina, André-Schmutz, Isabelle, Durandy, Anne, Fischer, Alain, Oksenhendler, Eric, Kracker, Sven
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.03.2019
• Subjects: 1-Phosphatidylinositol 3-kinase; Actin; Adaptive immunology; Age; AKT protein; Antibodies; B cells; B-Lymphocytes - immunology; B-Lymphocytes - pathology; Biomedical research; Bronchiectasis; Causes of; Cytoskeleton; Exome sequencing; Female; Genetic aspects; Genetics; Germinal Center - immunology; Germinal Center - pathology; Germinal centers; Guanine; Guanine nucleotide exchange factor; Human genetics; Humans; Immunodeficiency; Immunologic Memory - genetics; Immunological memory; Immunology; Infection; Infections; Life Sciences; Lymph nodes; Lymphocytes; Lymphocytes B; Lymphocytes T; Male; Memory cells; Muscle proteins; Mutation; Myelocytes; Myeloid cells; Nucleotides; Patients; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - immunology; Phosphorylation; Polymerization; Primary Immunodeficiency Diseases - genetics; Primary Immunodeficiency Diseases - immunology; Primary Immunodeficiency Diseases - pathology; Proteins; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - immunology; Purines; Recurrence (Disease); Respiratory tract diseases; Respiratory tract infections; Rho Guanine Nucleotide Exchange Factors - deficiency; Rho Guanine Nucleotide Exchange Factors - immunology; Rho-associated kinase; rho-Associated Kinases - genetics; rho-Associated Kinases - immunology; rhoA GTP-Binding Protein - genetics; RhoA protein; Risk factors; Siblings; Signal Transduction - genetics; Signal Transduction - immunology; T-Lymphocytes - immunology; T-Lymphocytes - pathology; Adaptive immunity; Immunology; B cells; Genetic diseases
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI120572

ARHGEF1 is a RhoA-specific guanine nucleotide exchange factor expressed in hematopoietic cells. We used whole-exome sequencing to identify compound heterozygous mutations in ARHGEF1, resulting in the loss of ARHGEF1 protein expression in 2 primary antibody-deficient siblings presenting with recurrent severe respiratory tract infections and bronchiectasis. Both ARHGEF1-deficient patients showed an abnormal B cell immunophenotype, with a deficiency in marginal zone and memory B cells and an increased frequency of transitional B cells. Furthermore, the patients' blood contained immature myeloid cells. Analysis of a mediastinal lymph node from one patient highlighted the small size of the germinal centers and an abnormally high plasma cell content. On the molecular level, T and B lymphocytes from both patients displayed low RhoA activity and low steady-state actin polymerization (even after stimulation of lysophospholipid receptors). As a consequence of disturbed regulation of the RhoA downstream target Rho-associated kinase I/II (ROCK), the patients' lymphocytes failed to efficiently restrain AKT phosphorylation. Enforced ARHGEF1 expression or drug-induced activation of RhoA in the patients' cells corrected the impaired actin polymerization and AKT regulation. Our results indicate that ARHGEF1 activity in human lymphocytes is involved in controlling actin cytoskeleton dynamics, restraining PI3K/AKT signaling, and confining B lymphocytes and myelocytes within their dedicated functional environment.