Several lines of evidence suggest that alterations of basement membrane structure may underlie the clinical and morphologic changes observed in adult polycystic kidney disease (APKD). The proposed studies are designed to answer the question: Do mutation in one or more of the genes encoding basement membrane proteins [Type IV collagen laminin, nidogen, entactin, or heparan sulfate proteoglycan (HSPG) core protein] cause (APKD)? The following approaches are proposed: (1) The structure and organization of the genes encoding the major basement membrane proteins in an APKD population will be determined by Southern blot analysis. Unusual patterns will be compared to those seen in a panel of controls to determine if the former are the result of gross gene alterations. Human cDNA probes for pro Alpha1(IV) collagen and laminin chain B1 are currently available for these studies. Murine genes for laminin A and B2, nidogen, entactin, and HSPG core protein will be used to isolate the homologous human cDNA probes. (2) More subtle alterations in the structure of these genes will be detected by linkage analysis. Large families with multiple affected individuals will be examined for cosegregation of a the APKD phenotype and specific gene alleles whose inheritance is detected by polymorphic restriction sites. Three large, multi-generation families are suitable for these studies; other families will be ascertained and characterized in the early phase of the proposed project. (3) In individual or families in whom either (1) or (2) indicates mutation in one of the genes interest, studies of mRNA encoded by this gene will be performed to pinpoint the region involved in the mutation. (4) Mutant genes identified by either (1) or (2) will be cloned and sequenced to demonstrate the nature of the mutation. (5) Oligonucleotide probes will be synthesized for mutant and normal alleles and used to study multiple families in an effort to determine the extent of genetic heterogeneity in APKD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK037065-02
Application #
3235771
Study Section
Pathobiochemistry Study Section (PBC)
Project Start
1986-07-01
Project End
1989-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
2
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Francomano, C A; Pyeritz, R E (1988) Achondroplasia is not caused by mutation in the gene for type II collagen. Am J Med Genet 29:955-61