A novel gross deletion in SMARCAL1 impairs DNA replication fork regression, leading to severe Schimke immuno-osseous dysplasia; a literature review and an integrated study of clinical, genetic, and protein-protein interaction analysis

Schimke immuno-osseous dysplasia (SIOD) is an exceptionally rare autosomal recessive disorder that affects multiple organ systems, most notably the skeletal system, kidneys, and immune system. The clinical manifestations of SIOD include growth retardation, skeletal deformities, progressive proteinuria, and immunodeficiency. Severe cases may progress to nephrotic syndrome and cerebral infarctions. The disorder is primarily attributed to biallelic mutations in the SMARCAL1 gene, which leads to the early onset of symptoms and often results in premature mortality. In this study, we identified a novel gross deletion encompassing exons 5 and 6 of the SMARCAL1 gene. This deletion leads to a partial loss of the HARP1 and HARP2 domains and the generation of a novel HARP domain that is structurally similar to both HARP1 and HARP2, while retaining conserved amino acids. Our AlphaFold 3D modeling indicated that the truncated SMARCAL1 protein is identical to the wild-type SMARCAL1, except for the absence of HARP1 domain, and resembles invertebrate SMARCAL1, which naturally possesses only one HARP domain. Previous studies have demonstrated that human SMARCAL1 lacking the HARP1 domain retains normal helicase, ATPase, and DNA-binding activities. Additionally, invertebrate SMARCAL1, which also lacks the HARP1 domain, fails to effectively regress DNA replication forks. This suggests that the identified gross deletion may contribute to SIOD pathogenesis by impairing DNA replication fork regression and genomic instability