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

J Clin Invest. 2012 Sep;122(9):3239-47. doi: 10.1172/JCI62949. Epub 2012 Aug 1.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Base Sequence
  • Betapapillomavirus
  • Case-Control Studies
  • Codon, Nonsense
  • Consanguinity
  • Disease Susceptibility
  • Epidermodysplasia Verruciformis / genetics*
  • Epidermodysplasia Verruciformis / immunology
  • Epidermodysplasia Verruciformis / pathology
  • Epidermodysplasia Verruciformis / virology
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Integrins / metabolism
  • Lymphocyte Count
  • Mice
  • Mice, Knockout
  • Pedigree
  • Polymorphism, Single Nucleotide
  • Receptors, Antigen, T-Cell / metabolism
  • Sequence Analysis, DNA
  • Signal Transduction
  • T-Lymphocytes / pathology*
  • Transcription Factors / deficiency*
  • Transcription Factors / genetics
  • rho GTP-Binding Proteins / deficiency*
  • rho GTP-Binding Proteins / genetics


  • Codon, Nonsense
  • Integrins
  • Receptors, Antigen, T-Cell
  • RhoH protein, human
  • Transcription Factors
  • rho GTP-Binding Proteins