Year: 2012
Type: article
Abstract: Epidermodysplasia verruciformis (EV) is a rare genetic disorder characterized by increased susceptibility to specific human papillomaviruses, the betapapillomaviruses. These EV-HPVs cause warts and increase the risk of skin carcinomas in otherwise healthy individuals. Inactivating mutations in epidermodysplasia verruciformis 1 (EVER1) or EVER2 have been identified in most, but not all, patients with autosomal recessive EV. We found that 2 young adult siblings presenting with T cell deficiency and various infectious diseases, including persistent EV-HPV infections, were homozygous for a mutation creating a stop codon in the ras homolog gene family member H (RHOH) gene. RHOH encodes an atypical Rho GTPase expressed predominantly in hematopoietic cells. Patients' circulating T cells contained predominantly effector memory T cells, which displayed impaired TCR signaling. Additionally, very few circulating T cells expressed the β7 integrin subunit, which homes T cells to specific tissues. Similarly, Rhoh-null mice exhibited a severe overall T cell defect and abnormally small numbers of circulating β7-positive cells. Expression of the WT, but not of the mutated RHOH, allele in Rhoh-/- hematopoietic stem cells corrected the T cell lymphopenia in mice after bone marrow transplantation. We conclude that RHOH deficiency leads to T cell defects and persistent EV-HPV infections, suggesting that T cells play a role in the pathogenesis of chronic EV-HPV infections.
DOI: 10.1172/jci62949
Authors: Amandine Crequer, Anja Troeger, Etienne Patin, Cindy S. Ma, Capucine Picard, Vincent Pedergnana, Claire Fieschi, Annick Lim, Avinash Abhyankar, Laure Gineau, Ingrid Mueller-Fleckenstein, Monika Schmidt, Alain Taieb, James Krueger, Laurent Abel, Stuart G. Tangye, Gérard Orth, David A. Williams, Jean-Laurent Casanova, Emmanuelle Jouanguy
Institutions: Université Paris Descartes, Rockefeller University, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard University, Harvard Stem Cell Institute, UNSW Sydney, Hôpital Necker-Enfants Malades, Assistance Publique – Hôpitaux de Paris, Human Genetic of Infectious Diseases, Inserm, Sorbonne Paris Cité, Hôpital Saint-Louis, Université Paris Diderot, Institut Pasteur, Friedrich-Alexander-Universität Erlangen-Nürnberg, Centre Hospitalier Universitaire de Bordeaux, Biotherapy of Genetic Diseases, Inflammatory Disorders and Cancers, Université Bordeaux Segalen, Centre National de la Recherche Scientifique, Department of Genomes & Genetics
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
Funders: St. Giles Foundation, Georgia Clinical and Translational Science Alliance, Deutsche Forschungsgemeinschaft, Institut National de la Santé et de la Recherche Médicale, Akademie der Wissenschaften und der Literatur, Mainz, William Lawrence and Blanche Hughes Foundation, National Institutes of Health, Medical Research Council, National Health and Medical Research Council, National Cancer Institute, National Center for Research Resources, National Center for Advancing Translational Sciences
OpenAlex ID: W2035754589