ADPKD Connective Tissue Disorder Link

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DESCRIPTION (provided by applicant): We have discovered a novel microfibril protein, named vascular matrix protein (VMP) which is extensively expressed in the media of large to medium sized blood vessels. Our evidence indicates that this protein is an alternative transcript arising from the PKD1 locus, the gene that codes for. Several lines of evidence support the conclusion that VMP is a component of matrix microfibrils. Extraction of VMP from tissue requires conditions similar to that described for other microfibril components such as fibrillin 1, 2, microfibril associated glycoprotein and elastin. VMP co-localized with fibrillin-1, fibrillin-2, elastin and microfibril associated glycoprotein (MAGP-1) as determined by immunohistochemistry and electron microscopy. Tissue etching with 6 M guanidinium chloride optimizes immunofluorescence labeling of tissue with anti-VMP. Discovery of VMP may account for the extra-renal manifestations of ADPKD which bears similarities to connective tissue disorders. Mutations in VMP may also account for the description of 2 families with ADPKD and connective tissue disorders. Strikingly these families phenotypically resemble a Marfan phenotype, yet their overlap connective tissue disorder linked to the PKD1 locus on chromosome 16 (Somlo et al., JASN, vol 4, 1371-8, 1993). Identification of another transcript encoded which codes for an extracellular matrix microfibril may also explain the finding that PKD1 knockout mice, generated by deletions from the 3' end of PKD1, have a fetal lethal phenotype due to increased vascular permeability, cardiac defects and subcutaneous hemorhages (Kim et al., PNAS, vol 97, 1731-35, 2000). VMP is ectopically expressed in the renal interstitium only in the setting of kidney cyst formation. This suggests that VMP expression is linked to epithelial growth abnormalities that lead to cyst formation. The goals of this proposal are to unambiguously identify the gene that codes for VMP, determine the biogenesis of VMP and examine its potential role in cystogenesis or nephrogenesis. RELEVANCE TO PUBLIC HEALTH-Polycystic kidney disease is the most common genetic cause of renal failure in the United States. Better understanding of the disease process will lead to therapies that halt progression of renal failure thereby decreasing the number of patients on dialysis.