Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 122, Issue 9, Pages 3239-3247Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI62949
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Funding
- INSERM
- University Paris Descartes
- Rockefeller University
- Rockefeller University Clinical and Translational Science Awards (CTSA) [5UL1RR024143]
- St. Giles Foundation
- National Health and Medical Research Council of Australia
- Deutsche Forschungsgemeinschaft [TR 1005/1-1]
- William Lawrence and Blanche Hughes Foundation
- NIH [5R01CA113969-08]
- Akademie der Wissenschaften und der Literatur, Mainz, Germany
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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 beta(7) 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 beta(7)-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.
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