application) Nephrotic syndrome (NS) is characterized by massive loss of protein in the urine, hypoalbuminemia and generalized swelling. It is a pathological entity of unknown etiology which usually occurs sporadically and has been reported in patients from all over the world. NS can be either primary or secondary. Minimal change NS (MCNS) and focal segmental glomerulosclerosis (FSGS) are amongst the major causes of primary NS especially in children. The two entities have been considered to be different ends of the spectrum of the same disease especially since MCNS has been shown to progress to FSGS in various studies. FSGS is a significant cause of renal disease (ESRD) comprising up to 5% of adults and 20% of children with ESRD. Besides the primary form, FSGS can also occur secondary to other conditions such as reflux nephropathy, AIDS and sickle cell disease. Thus NS/FSGS can occur in the setting of a number of diverse medical conditions besides the idiopathic form, and genetic factors have been implicated in its etiopathogenesis in a number of various studies and familial cases have been reported. In the reported familial cases both autosomal dominant and recessive forms have been identified with the dominant forms being generally less severe than the recessive forms. Thus NS appears to be a group of heterogeneous disorders with very little information available on the responsible genes. Hence, elucidation of gene(s) associated with various heritable forms of NS will allow greater understanding of its etiopathogenesis and possibly also of the more common sporadic NS/FSGS. It will likely lead to a more precise classification and possibly to new therapeutic approaches. We recently found linkage between chromosome 19q 13 and an autosomal dominant form of NS in a large family hailing from the Pittsburgh area. We have also found an unusually high number of families (20 so far) within the Pittsburgh/Western Pennsylvania region with familial NS/FSGS. In addition we have ascertained more than twenty other families with familial NS/FSGS who will be the basis of this proposed study. Several of the families are large enough to provide information on responsible chromosomal region (linkage data) by themselves. We propose a detailed search for genes responsible for familial NS/FSGS. In this study we aim to evaluate mutations in several candidate genes (including nephrin, and actinin 4) located on chromosome 19q13 in autosomal dominant NS/FSGS families and aim to identify new genomic loci for NS/FSGS by linkage analysis for families not found linked to chromosome 19q markers. Further identification of candidate genes for familial NS/FSGS is proposed by positional candidate gene approaches and finally we aim to investigate the role of the gene(s) found to be responsible for familial NS/FSGS in the etiopathogenesis of the more common sporadic NS/FSGS.
