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Cited by 159Immunodeficiency and Autoimmune DisordersT-cell and B-cell ImmunologyGenetic and rare skin diseases.

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

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Crequer, Amandine, Troeger, Anja, Patin, Etienne, Ma, Cindy S., Picard, Capucine, Pedergnana, Vincent, Fieschi, Claire, Lim, Annick +12 more·2012·Journal of Clinical Investigation
DOI 10.1172/jci62949PMC PMC3428089
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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.

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  • Our patient's immunophenotype shared similarities with previously reported RHOH deficiency cases in terms of reduced CD4+ T cells, increased CD8+ T cells, and an elevated proportion of activated, differentiated effector and memory CD8+ T cells.

    “Our patient's immunophenotype shared similarities with previously reported RHOH de ciency cases in terms of reduced CD4 + T cells, increased CD8 + T cells, and an elevated proportion of activated, differentiated effector and memory CD8 + T cells.”

    From A Novel Homozygous RHOH Variant Associated with T Cell Dysfunction and Recurrent Opportunistic Infections (2024) · cites this paper as [6]

    In ‘Impact of human RHOH deficiency on T cells’ (page unavailable), the paper reports slightly lower CD4+ and higher CD8+ T-cell frequencies in both patients, along with increased effector-memory and revertant-memory CD8+ subsets. It describes the expanded memory cells as showing signs of exhaustion, but does not establish an elevated proportion of activated CD8+ T cells. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Previously, a homozygous nonsense Y38X mutation in RHOH was reported in siblings suffering from epidermodysplasia verruciformis, increased susceptibility to certain HPV, lung disease, Burkitt lymphoma and impaired T-cell function.

    “Previously, a homozygous nonsense Y38X mutation in the RHOH gene (GenBank: NM_004310.5:c.114C > G, p.Tyr38Ter) was reported in siblings suffering from epidermodysplasia verruciformis, increased susceptibility to certain human papillomaviruses (HPV), lung disease, Burkitt lymphoma and impaired T-cell function (MIM: 618307) (6).”

    From A Novel Homozygous RHOH Variant Associated with T Cell Dysfunction and Recurrent Opportunistic Infections (2024) · cites this paper as [6]

    The mutation-identification section reports a homozygous RHOH Y38X nonsense mutation in two siblings with persistent EV-HPV infections and T-cell defects. The Introduction and Methods specify that bronchopulmonary disease and Burkitt lymphoma occurred in P1, not both siblings; the Introduction also describes their phenotype as related to, but distinct from, epidermodysplasia verruciformis. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The Y38X variant led to a complete loss of RHOH protein expression.

    “The Y38X variant led to a complete loss of RHOH protein expression.”

    From A Novel Homozygous RHOH Variant Associated with T Cell Dysfunction and Recurrent Opportunistic Infections (2024) · cites this paper as [6]

    In ‘Identification of a nonsense mutation in the RHOH gene,’ the authors report that the 21-kDa RHOH protein was absent from both patients’ T cells and that no protein was detected from Y38X-transfected cells. They also state that translation reinitiation cannot be formally excluded, so the evidence supports loss of detectable full-length protein but not an unqualified complete loss of all RHOH protein expression. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • To date, only one kindred of RHOH deficiency, also called epidermodysplasia verruciformis-4, has been documented.

    “To date, only one kindred of RHOH de ciency, also called epidermodysplasia verruciformis-4, has been documented (6).”

    From A Novel Homozygous RHOH Variant Associated with T Cell Dysfunction and Recurrent Opportunistic Infections (2024) · cites this paper as [6]

    The Discussion (page unavailable) reports the discovery of RHOH deficiency in one kindred, and the Abstract identifies two affected siblings. The paper does not call the condition epidermodysplasia verruciformis-4 or establish that this remained the only documented kindred at the citing paper’s date. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Disruption of RHOH gene has been associated with various types of B-cell malignancies and inborn errors of immunity.

    “Disruption of RHOH (MIM: 602037) gene has been associated with various types of B-cell malignancies (4) and inborn errors of immunity (IEI) (6).”

    From A Novel Homozygous RHOH Variant Associated with T Cell Dysfunction and Recurrent Opportunistic Infections (2024) · cites this paper as [6]

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Cites

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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.
Affiliations
  • Boston Children's Hospital (US)
  • UNSW Sydney (AU)
  • Inserm (FR)
  • Sorbonne Paris Cité (FR)
  • Institut Pasteur (FR)
  • Rockefeller University (US)
  • Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
  • Hôpital Necker-Enfants Malades (FR)
  • Human Genetic of Infectious Diseases (FR)
  • Centre National de la Recherche Scientifique (FR)
Corresponding author
Jouanguy, Emmanuelle
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2012-09-04
Volume
122
Issue
9
Pages
3239-3247
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci62949
PMC
PMC3428089
OpenAlex
W2035754589
Cited by
159
References
2
Citations by year
2026: 3 · 2025: 12 · 2024: 7 · 2023: 8 · 2022: 12 · 2021: 14 · 2020: 19 · 2019: 7 · 2018: 13 · 2017: 10 · 2016: 16 · 2015: 9 · 2014: 16 · 2013: 10 · 2012: 3
FWCI
4.99
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Funders
  • St. Giles Foundation
  • Georgia Clinical and Translational Science Alliance
  • Deutsche Forschungsgemeinschaft (TR 1005/1-1)
  • 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 (U54TR001005)
  • Medical Research Council
  • National Health and Medical Research Council
  • National Cancer Institute (R01CA113969)
  • National Center for Research Resources (UL1RR024143)
  • National Center for Advancing Translational Sciences
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and rare skin diseases.
Keywords
epidermodysplasia verruciformis, human papillomavirus, T cell deficiency, T-cell lymphopenia, T cell receptor signaling, beta7 integrin, effector memory T cells, Rho GTPases, bone marrow transplantation, viral persistence
MeSH terms
Adult, Animals, Base Sequence, Consanguinity, Disease Susceptibility, Epidermodysplasia Verruciformis, Genotype, Humans, Pedigree, Receptors, Antigen, T-Cell, T-Lymphocytes, Transcription Factors, Signal Transduction, Case-Control Studies, Integrins, Sequence Analysis, DNA, Mice, Knockout, Codon, Nonsense, Lymphocyte Count, Polymorphism, Single Nucleotide, rho GTP-Binding Proteins, Mice, Betapapillomavirus, Genome-Wide Association Study

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