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Human RHOH deficiency causes T cell defects and susceptibility to EV-HPV infections


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 beta7 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 beta7-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.

Type Journal
Authors Crequer, A.; Troeger, A.; Patin, E.; Ma, C. S.; Picard, C.; Pedergnana, V.; Fieschi, C.; Lim, A.; Abhyankar, A.; Gineau, L.; Mueller-Fleckenstein, I.; Schmidt, M.; Taieb, A.; Krueger, J.; Abel, L.; Tangye, S. G.; Orth, G.; Williams, D. A.; Casanova, J. L.; Jouanguy, E.;
Published Date 2012-09-02
Published Volume 0122
Published Issue 9
Published Pages 3239-47
Status Published in-print
DOI 10.1172/JCI62949
URL link to publisher's version
OpenAccess link to author's accepted manuscript version