Defects in the COL4A5 gene, which encodes the distinct basement membrane collagen alpha5(V), have recently been demonstrated in Alport Syndrome (AS), a hereditary progressive glomerulonephritis. The disease shows substantial phenotypic variation, similar to osteogenesis imperfecta, where various defects in COL1A1 and COL1A2 cause bone fragility with a very wide range of phenotypic severity. In AS, the disease varies with respect to the severity of associated deafness, the age of onset and end-stage renal disease (which requires kidney transplant or permanent dialysis therapy), and the presence of characteristic eye and blood abnormalities. The variability of hearing loss appears to be due to allelic variation at COL4A5, since two mutations which lie entirely within the gene cause deafness of different severities. The applicants propose to perform genetic studies to determine if the genetic defect in any Alport family is at a locus other than COL4A5. As part of a collaborative effort, the applicants will examine the COL4A5 gene for mutation in families where the defect appears to reside at this locus. Comprehensive clinical characterization of these families by collaborators will be conducted and together these studies will form the basis for a correlation of the molecular defects with the variable phenotypes. Establishing this correlation will improve the efficacy of therapeutic intervention in the disease and lead to a better understanding of the role of COL4A5 in the molecular architecture of the basement membrane, perhaps suggesting some means of intervening in the progressive disease process. The circumstances of the origin of new COL4A5 mutations will also be examined to determine if there are any important risk factors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK043761-01A1
Application #
3245238
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1992-03-01
Project End
1995-02-28
Budget Start
1992-03-01
Budget End
1993-02-28
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Utah
Department
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Barker, D F; Denison, J C; Atkin, C L et al. (2001) Efficient detection of Alport syndrome COL4A5 mutations with multiplex genomic PCR-SSCP. Am J Med Genet 98:148-60
Barker, D F; Denison, J C; Atkin, C L et al. (1997) Common ancestry of three Ashkenazi-American families with Alport syndrome and COL4A5 R1677Q. Hum Genet 99:681-4
Barker, D F; Pruchno, C J; Jiang, X et al. (1996) A mutation causing Alport syndrome with tardive hearing loss is common in the western United States. Am J Hum Genet 58:1157-65
Fain, P R; Kort, E N; Chance, P F et al. (1995) A 2D crossover-based map of the human X chromosome as a model for map integration. Nat Genet 9:261-6
Barker, D F; Cordray, P; Fain, P R (1994) The same polymorphism identified by the DXS571(B) and DXS1105 loci. Hum Mol Genet 3:1913
Zhou, J; Gregory, M C; Hertz, J M et al. (1993) Mutations in the codon for a conserved arginine-1563 in the COL4A5 collagen gene in Alport syndrome. Kidney Int 43:722-9