SMARCAL1 – Schimke Immuno-osseous Dysplasia

Schimke immuno-osseous dysplasia (SIOD) is a pleiotropic autosomal recessive disorder defined by spondyloepiphyseal dysplasia, steroid-resistant nephrotic syndrome, and T-cell immunodeficiency. The causative gene, SMARCAL1, encodes an annealing helicase involved in replication fork maintenance and chromatin remodeling ( PMID:11799392 ).

Pathogenic biallelic SMARCAL1 variants have been reported in over 125 patients across 26 unrelated families, demonstrating consistent autosomal recessive inheritance and multi-family segregation ( PMID:11799392 ; PMID:39113392 ).

The variant spectrum includes nonsense, frameshift, splice-site, and missense changes distributed throughout the coding sequence. Missense variants such as c.836T>C (p.Phe279Ser) are associated with milder phenotypes, while truncating and splice-site variants correlate with severe early-onset forms of SIOD ( PMID:16237566 ).

Functional assays reveal that SMARCAL1 missense mutants exhibit reduced ATPase activity, impaired DNA binding, and defective replication fork stabilization. SMARCAL1 deficiency in zebrafish results in cell-cycle arrest and recapitulates skeletal, vascular, and hematopoietic defects observed in SIOD patients ( PMID:20036229 ; PMID:18805831 ).

Some SIOD patients lack detectable SMARCAL1 coding variants, suggesting locus heterogeneity or deep intronic/regulatory mutations outside diagnostic assays ( PMID:17089404 ). These findings underscore the need for comprehensive genomic testing in clinically suspected SIOD.

In summary, genetic and functional evidence definitively implicates SMARCAL1 loss-of-function in SIOD pathogenesis. Molecular testing of SMARCAL1 should be considered in patients with compatible phenotypes to guide diagnosis, prognosis, and management.

Key Take-home: Biallelic SMARCAL1 variants cause SIOD; genetic confirmation enables targeted care and accurate genetic counselling.

References

• Nature Genetics | 2002 | Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia PMID:11799392
• Journal of Clinical Research in Pediatric Endocrinology | 2025 | Expanding the Clinical Features of Schimke Immuno-Osseous Dysplasia: a New Patient with a Novel Variant and Novel Clinical Findings PMID:39113392
• Pediatric Nephrology | 2005 | R561C missense mutation in the SMARCAL1 gene associated with mild Schimke immuno-osseous dysplasia PMID:16237566
• Developmental Biology | 2010 | Deficiency of smarcal1 causes cell cycle arrest and developmental abnormalities in zebrafish PMID:20036229
• Journal of Medical Genetics | 2009 | Schimke immuno-osseous dysplasia: SMARCAL1 loss-of-function and phenotypic correlation PMID:18805831
• Human Mutation | 2007 | Schimke immunoosseous dysplasia: suggestions of genetic diversity PMID:17089404

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