An inborn error in epidermal growth factor prohormone metabolism in a mouse model of autosomal recessive polycystic kidney disease.
The C57BL/6J CPK heterozygous breeders secrete in urine a variant EGF-prohormone with a molecular mass of 154 kDa in addition to the normal 165 kDa EGF-prohormone. The 154 kDa prohormone is secreted as a heterodimer with the normal 165 kDa prohormone. The phenotypically normal littermates, like their parents, secrete the 154 and 165 kDa EGF-prohormones in urine while their cystic siblings secrete neither protein. Examination of renal extracts of normal littermates revealed the presence of the 165 kDa but not the 154 kDa EGF-prohormone; renal extracts of cystic siblings contained neither protein. Cyst fluid, however, contained 56 and 49 kDa EGF-immunoreactive proteins in high concentrations. The data suggest that in the absence of normal 165 kDa prohormone, the 154 kDa EGF-prohormone undergoes proteolysis and that the resultant fragments function as cystogens. Since normal siblings do not acquire renal cystic disease despite expressing the variant 154 kDa EGF-prohormone while the affected littermates, which lack the normal 165 kDa EGF-prohormone, manifest renal cystic disease, we suggest that congenital polycystic kidney disease is due to an inborn defect in the synthesis and secretion of the normal 165 kDa renal EGF-prohormone.
Lakshmanan
J
J
Department of Pediatrics, Harbor-UCLA Medical Center, Torrance 90509.
Fisher
D A
DA
D000328:Adult; D000818:Animals; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D004815:Epidermal Growth Factor / Q000378:metabolism* / Q000652:urine*; D005260:Female; D005808:Genes, Recessive; D006579:Heterozygote; D006801:Humans; D046911:Macromolecular Substances; D008297:Male; D008661:Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism* / Q000652:urine; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D008970:Molecular Weight; D010641:Phenotype; D007690:Polycystic Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000652:urine; D011498:Protein Precursors / Q000378:metabolism* / Q000652:urine*; D012016:Reference Values
D046911:Macromolecular Substances; D011498:Protein Precursors; C042652:epidermal growth factor precursor; D004815:Epidermal Growth Factor