(Taken directly from the application) Absorptive hypercalciuria (AH) is the most common cause of nephrolithiasis present in about 50% of patients with recurrent disease. Both clinical and experimental data indicate that the disease is heterogeneous in origin. However, evidence is strong regarding involvement of a genetic process in AH, with a familial pattern being demonstrated in 45% of reported stone cases. The belief in the genetic predisposition to AH underlies our continuing search for the molecular defect(s) in this condition. The overall goal for this application is to identify the gene defect (s) associated with absorptive hypercalciuria. Clinically, an invariant feature of absorptive hypercalciuria is the intestinal hyperabsorption of calcium. It is now recognized that bone loss, particularly of cancellous bone, frequently occurs in absorptive hypercalciuria. Both of these clinical manifestations of AH must be accommodated by any genetic defect(s) proposed for absorptive hypercalciuria. This application will examine three possible molecular mechanisms to explain the pathophysiology of AH using a combination candidate gene approach and genome wide screening based on linkage analysis. One scheme implicates a central intestinal cell defect due to a variety of vitamin D-related or vitamin D-regulated genes. The second scheme involves a bone defect due to abnormal cytokine production or activity, or vitamin D-response element mutation.
Aim 2, will therefore focus on patients with low bone density attempting by combination of histological and molecular techniques to identify the molecular basis of this defect. The third scheme suggest that a mutation of an unidentified gene is responsible for both intestinal and skeletal defects.
In Aim 3, a genome-wide search for the gene defect associated with the intestinal and skeletal lesions of AH will be performed in well defined kindreds with absorptive hypercalciuria, by linkage analysis and positional cloning. Due to the apparent heterogeneity of absorptive hypercalciuria a careful metabolic evaluation is required to provide an improved phenotype characterization for all genetic analyses. The goal of Aim 4 is to provide a detailed metabolic and clinical evaluation of all participating patients and family members for improved phenotype depiction.
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