PATHOGENESIS OF ALPORT SYNDROME

Beth Israel Deaconess Medical Center, Boston MA

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Linked publications & trials

Abstract

Alport syndrome (AS) in an inherited disorder caused by mutations in the C0L4A3, C0l4A4, or C0L4A5 genes. X-linked AS (XAS) is due to a defective alpha-5 chain, while an autosomal recessive form of AS is due to mutations in C0L4A3. The pathology is indistinguishable for the two forms, suggesting a common mode of breakdown of the glomerular basement membrane (GBM). The precise mechanism for GBM deterioration in both forms is unknown, but it is likely due to deficiencies in alpha chain protomer assembly. We propose to generate two mouse models for AS which should provide the opportunity to dissect the molecular events leading to renal failure in these patients. A transgenic mouse will be generated that expresses the alpha-3 (IV) NC1 domain in podocytes. Chain association studies will be performed in this in vivo model which should present with Alport-like symptoms, due to a dominant negative mechanism. Additionally, a C0L4A5- deficient mouse will be generated to study the role of the alpha- 5 (IV) chain in the assembly and integrity of the GBM. We will analyze the glomeruli of these animals using protein biochemical techniques to help elucidate the mechanism for GBM breakdown in AS.