AccScience Publishing / GPD / Online First / DOI: 10.36922/GPD025480078
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REVIEW ARTICLE

Genetic alterations in Schimke immunoosseous dysplasia: Pathogenic mechanisms and therapeutic prospects

Kamil A. Sobieszek1,2* ,  Patrycja Idzik3
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1 Student Scientific Group at The Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland
2 Foundation of Prof. Jerzy Sadowski “SERCE dla WIEDZY”, Lesser Poland Specialist Clinics UniCardia & UniMedica & UniEstetica, Krakow, Poland
3 Department of Biology, Institute of Biology and Earth Sciences, University of National Education Commission, Krakow, Poland
GPD, 025480078 https://doi.org/10.36922/GPD025480078
Received: 25 November 2025 | Revised: 30 January 2026 | Accepted: 4 February 2026 | Published online: 6 March 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Schimke immuno-osseous dysplasia (SIOD) is an ultra-rare autosomal recessive multisystem disorder caused by biallelic pathogenic variants in SMARCAL1, which encodes an adenosine triphosphate-dependent annealing helicase involved in replication-fork remodeling and chromatin dynamics. Loss of SMARCAL1 function leads to replication-associated genomic instability, transcriptional dysregulation, and telomere dysfunction, collectively underlying the triad of steroid-resistant nephrotic syndrome, spondyloepiphyseal dysplasia, and T-cell immunodeficiency, as well as vascular and malignant complications. In this review, we summarize the spectrum of SMARCAL1 genetic alterations in SIOD, ranging from missense and truncating variants to gross deletions, and discuss their molecular consequences at the protein and cellular levels. We highlight current disease models, including patient-derived induced pluripotent stem cells (iPSCs) and inducible SMARCAL1 knockdown iPSC systems, which have revealed mechanistic links between replication stress and dysregulated expression of master differentiation genes. Finally, we evaluate the state of the art and realistic prospects for gene therapy in SIOD. Although no gene therapy trial for SIOD is currently active, advances in iPSC modeling, clustered regularly interspaced short palindromic repeats-mediated gene correction, and successful ex vivo hematopoietic stem cell gene therapy in related monogenic immunodeficiencies position SMARCAL1 as a plausible, though challenging, therapeutic target. Key obstacles include multi-organ involvement, strict control of SMARCAL1 dosage due to its role in genome stability, and the extreme rarity of the disorder, which limits the feasibility of clinical trials.

Keywords
Schimke immuno-osseous dysplasia
Immune-osseous dysplasia
SMARCAL1
Immunodeficiency
Gene therapy
CRISPR
Funding
None.
Conflict of interest
The authors declare that they have no competing interests.
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