title: Human RHOH deficiency causes T cell defects and susceptibility to EV-HPV infections.
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.
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA.
authors.forename: Amandine
authors.initials: A
authors.lastname: Crequer
authors.forename: Anja
authors.initials: A
authors.lastname: Troeger
authors.forename: Etienne
authors.initials: E
authors.lastname: Patin
authors.forename: Cindy S
authors.initials: CS
authors.lastname: Ma
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Vincent
authors.initials: V
authors.lastname: Pedergnana
authors.forename: Claire
authors.initials: C
authors.lastname: Fieschi
authors.forename: Annick
authors.initials: A
authors.lastname: Lim
authors.forename: Avinash
authors.initials: A
authors.lastname: Abhyankar
authors.forename: Laure
authors.initials: L
authors.lastname: Gineau
authors.forename: Ingrid
authors.initials: I
authors.lastname: Mueller-Fleckenstein
authors.forename: Monika
authors.initials: M
authors.lastname: Schmidt
authors.forename: Alain
authors.initials: A
authors.lastname: Taieb
authors.forename: James
authors.initials: J
authors.lastname: Krueger
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Tangye
authors.forename: Gérard
authors.initials: G
authors.lastname: Orth
authors.forename: David A
authors.initials: DA
authors.lastname: Williams
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Jouanguy
mesh_terms: D000328:Adult; D000818:Animals; D001483:Base Sequence; D052686:Betapapillomavirus; D016022:Case-Control Studies; D018389:Codon, Nonsense; D003241:Consanguinity; D004198:Disease Susceptibility; D004819:Epidermodysplasia Verruciformis / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000821:virology; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D016023:Integrins / Q000378:metabolism; D018655:Lymphocyte Count; D051379:Mice; D018345:Mice, Knockout; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000473:pathology*; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics; D020741:rho GTP-Binding Proteins / Q000172:deficiency* / Q000235:genetics
chemical_list: D018389:Codon, Nonsense; D016023:Integrins; D011948:Receptors, Antigen, T-Cell; C447841:RhoH protein, human; D014157:Transcription Factors; D020741:rho GTP-Binding Proteins