OSCR

STAT2 R148 variant: A 16th-century founder mutation and clinical response to high-dose JAK inhibitor therapy.

Overview

Authors: Nima Parvaneh1, Rasol Molatefi2,3, Conor Gruber4,5,6, Sajjad Biglari7, Leila Moradi8, Yoann Seeleuthner9,10, Fatima Ailal11,12, Ahmed Aziz Bousfiha11,12, Neda Pak13, Camille Soudée9,10, Jean-Laurent Casanova9,10,14,15,16, Jérémie Rosain9,10,15,17, Dusan Bogunovic4,5,18, Mohammad Reza Fazlollahi8, Mohammad Shahrooei19, Jacinta Bustamante9,10,15,17
ORCID iDs: Nima Parvaneh, Rasol Molatefi, Conor Gruber, Sajjad Biglari, Leila Moradi, Yoann Seeleuthner, Fatima Ailal, Ahmed Aziz Bousfiha, Neda Pak, Camille Soudée, Jean-Laurent Casanova, Jérémie Rosain, Dusan Bogunovic, Mohammad Reza Fazlollahi, Mohammad Shahrooei, Jacinta Bustamante
19 affiliations
  1. Division of Allergy and Clinical Immunology, Department of Pediatrics, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
  2. Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
  3. Department of Pediatrics, Bo-Ali Children’s Hospital, Ardabil University of Medical Sciences, Ardabil, Iran
  4. Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
  5. Columbia Center for Genetic Errors of Immunity, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
  6. Division of Rheumatology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
  7. Farin Genetics Laboratory, Tehran, Iran
  8. Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran
  9. Imagine Institute, Paris Cité University, Paris, France
  10. Laboratory of Human Genetics of Infectious Diseases, INSERM U1163, Necker Hospital for Sick Children, Paris, France
  11. Laboratory of Clinical Immunology, Infection and Autoimmunity, Faculty of Medicine and Pharmacy of Casablanca, Hassan II University, Casablanca, Morocco
  12. Department of Pediatric Infectious Diseases and Clinical Immunology, Children’s Hospital, CHU Averroes, Casablanca, Morocco
  13. Radiology Department, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
  14. Department of Pediatrics, Necker Hospital for Sick Children, Paris, Assistance Publique-Hôpitaux de Paris, Paris, France
  15. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
  16. Howard Hughes Medical Institute, New York, NY, USA
  17. Center for the Study of Primary Immunodeficiencies, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris, Paris, France
  18. Division of Pediatric Allergy, Immunology and Rheumatology, Department of Pediatrics, Columbia University, New York, NY, USA
  19. Dr. Shahrooei Lab, Tehran, Iran
Institutions: Children's Medical Center (Iran); Tehran University of Medical Sciences (Iran); Ardabil University of Medical Sciences (Iran); Children's Hospital of Philadelphia (United States); Columbia University Irving Medical Center (United States); Columbia University (United States); Hôpital Necker-Enfants Malades (France); Inserm (France); Institut des Maladies Génétiques Imagine (France); University of Hassan II Casablanca (Morocco); Howard Hughes Medical Institute (United States); Assistance Publique – Hôpitaux de Paris (France); Rockefeller University (United States)
Journal: Journal of human immunity, volume 2, issue 4, article e20260001
Dates: received 1 January 2026; accepted 28 April 2026; published online 27 May 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.70962/jhi.20260001 · PMID 42212111 · PMCID PMC13215009 · OpenAlex W7162526733
Open access: diamond, a free copy (OpenAlex)
Status: data only
Categories: human (organism), clinical / translational (subfield)
Methods: fMRI & imaging
Topic: Immunodeficiency and Autoimmune Disorders (Immunology, Immunology and Microbiology), according to OpenAlex
Funding: St. Giles Foundation; French Agence Nationale de la Recherche (ANR-10-IAHU-01, ANR-10-LABX-62-IBEID); Rockefeller University; National Institute of Allergy and Infectious Diseases (R01AI095983, R37AI095983); NIAID NIH HHS (R37 AI095983); National Center for Advancement of Translational Sciences (UL1TR001866); Paris Cité University; NCATS NIH HHS (UL1 TR001866); Institut National de la Santé et de la Recherche Médicale
Citations: not cited yet (Europe PMC); 35 references in the paper

Abstract

STAT2 R148 variants cause severe type I interferonopathy by disrupting USP18-mediated negative feedback regulation. We studied two new Iranian patients homozygous for STAT2 p.R148Q variant presenting with life-threatening neuroinflammation and respiratory failure. Patient 1 developed seizures, brain calcifications, and severe pneumonia, achieving dramatic improvement with high-dose ruxolitinib. Patient 2 presented with lymphadenopathy, encephalitis, and recurrent infections and died from respiratory failure at 8.5 years. Haplotype and principal component analysis (PCA) analysis revealed a founder variant originating ∼491 years ago in the Middle East/North African region. A review of five published cases and these two patients demonstrated constant neurological involvement and a high mortality rate. Early recognition and high-dose JAK inhibitor therapy may improve outcomes in this devastating but potentially treatable interferonopathy.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

Tracing map

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Data

Datasets cited

Data availability

The genetic data for the patients in this study have been submitted to the ClinVar database under the accession link: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000907069.5.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 16 authors, 9 funders, 35 references.

Cite

This paper

Parvaneh, N., Molatefi, R., Gruber, C., Biglari, S., Moradi, L., Seeleuthner, Y., Ailal, F., Bousfiha, A. A., Pak, N., Soudée, C., Casanova, J.-L., Rosain, J., Bogunovic, D., Fazlollahi, M. R., Shahrooei, M., & Bustamante, J. (2026). STAT2 R148 variant: A 16th-century founder mutation and clinical response to high-dose JAK inhibitor therapy. Journal of human immunity, 2(4), e20260001. https://doi.org/10.70962/jhi.20260001

BibTeX

@article{parvaneh2026stat2,
author = {Parvaneh, Nima and Molatefi, Rasol and Gruber, Conor and Biglari, Sajjad and Moradi, Leila and Seeleuthner, Yoann and Ailal, Fatima and Bousfiha, Ahmed Aziz and Pak, Neda and Soudée, Camille and Casanova, Jean-Laurent and Rosain, Jérémie and Bogunovic, Dusan and Fazlollahi, Mohammad Reza and Shahrooei, Mohammad and Bustamante, Jacinta},
title = {{STAT2 R148 variant: A 16th-century founder mutation and clinical response to high-dose JAK inhibitor therapy}},
journal = {Journal of human immunity},
year = {2026},
month = may,
volume = {2},
number = {4},
pages = {e20260001},
publisher = {The Rockefeller University Press},
issn = {3065-8993},
doi = {10.70962/jhi.20260001},
url = {https://doi.org/10.70962/jhi.20260001},
pmid = {42212111},
pmcid = {PMC13215009}
}

RIS

TY - JOUR
AU - Parvaneh, Nima
AU - Molatefi, Rasol
AU - Gruber, Conor
AU - Biglari, Sajjad
AU - Moradi, Leila
AU - Seeleuthner, Yoann
AU - Ailal, Fatima
AU - Bousfiha, Ahmed Aziz
AU - Pak, Neda
AU - Soudée, Camille
AU - Casanova, Jean-Laurent
AU - Rosain, Jérémie
AU - Bogunovic, Dusan
AU - Fazlollahi, Mohammad Reza
AU - Shahrooei, Mohammad
AU - Bustamante, Jacinta
TI - STAT2 R148 variant: A 16th-century founder mutation and clinical response to high-dose JAK inhibitor therapy
T2 - Journal of human immunity
J2 - J Hum Immun
PY - 2026
DA - 2026/05/27
VL - 2
IS - 4
SP - e20260001
SN - 3065-8993
PB - The Rockefeller University Press
DO - 10.70962/jhi.20260001
UR - https://doi.org/10.70962/jhi.20260001
LA - en
ER -

CSL-JSON

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