Schimke immuno-osseous dysplasia: expression of SMARCAL1 in blood and kidney provides novel insight into disease phenotype.

Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive disorder caused by loss-of-function mutations in SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1), with clinical features of growth retardation, spondylo-epiphyseal dysplasia, nephrotic syndrome, and immunodeficiency. We report a patient with SIOD and SMARCAL1 splice mutation (IVS4-2 A>G) in a nonconsanguineous Ashkenazi family, who came to our attention at 1 mo of age due to renal malformation and only later developed signs compatible with Schimke. Interestingly, residual SMARCAL1 mRNA levels in the patient's peripheral blood were lower compared with those observed in both asymptomatic brothers' carrying the same bi-allelic mutation, whereas the latter had levels similar to those found in heterozygous carriers (parents and sister). Examination of the carrier frequency of the splice mutation in the Ashkenazi population demonstrated 1 carrier in 760 DNA samples. In situ localization of SMARCAL1 in human kidneys as well as analysis of its temporal expression during murine nephrogenesis and in the metanephric organ culture suggested a role in the early renal progenitor population and after renal maturation. Thus, disease severity within the same family might be modified by the splicing machinery. The renal expression pattern of SMARCAL1 explains a broader spectrum of renal disease in SIOD than previously described.