Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive spondylo-epiphyseal dysplasia characterized by 1) disproportionate short stature with hyperpigmented macules and dysmorphic facial features, 2) proteinuria with progressive renal failure and 3) lymphopenia with defective cellular immunity. In addition, patients with SIOD have a high incidence of thyroid dysfunction, bone marrow hypoplasia, ocular abnormalities, and cerebral ischemia. The progressive renal failure, immunodeficiency, bone marrow hypoplasia and cerebral ischemia cause significant morbidity and mortality. Dialysis and renal transplantation are the only effective treatments for the progressive renal failure and bone marrow transplantation for the blood cytopenia. There are no effective therapies for the growth failure and cerebral ischemia. Nearly all patients die within the first 15 years of life.Over the past 5 years, I have collected DNA samples and clinical information on SIOD patients from 26 families. Using four families in which the parents were consanguineous, I have recently completed a genome-wide screen and mapped SIOD to chromosome 2q34-q35. Subsequently by a candidate gene approach, I have identified recessive mutations in the SMARCAL1 gene in 26 unrelated SIOD patients. The SMARCAL1 protein, which is an SNF2 protein, has ATPase activity in the presence of single stranded DNA, but its function is otherwise undefined. The goal of this proposal is to identify proteins interacting with SMARCAL1 and to define the function of conserved amino acids; this research is an excellent adjunct to my K08 which is focused on using the power of Drosophila melanogaster genetics to define the pathways within which SMARCAL1 operates. This combined genetic and biochemical approach to delineating the function of SMARCAL1 will increase our understanding of the biology of SMARCAL1 and it regulation of organism development as well as provide insight into the mechanism by which mutations in this gene can give rise to SIOD.
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