An inborn error in epidermal growth factor prohormone metabolism in a mouse model of autosomal recessive polycystic kidney disease.

Abstract

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.

• Authors: J Lakshmanan, D A Fisher
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 196 Issue 2 Pg. 892-901 (Oct 29 1993) ISSN: 0006-291X [Print] United States
• PMID: 8240367 (Publication Type: Journal Article)

Chemical References

• Macromolecular Substances
• Protein Precursors
• epidermal growth factor precursor
• Epidermal Growth Factor

Topics

• Adult
• Animals
• Disease Models, Animal
• Electrophoresis, Polyacrylamide Gel
• Epidermal Growth Factor (metabolism, urine)
• Female
• Genes, Recessive
• Heterozygote
• Humans
• Macromolecular Substances
• Male
• Metabolism, Inborn Errors (genetics, metabolism, urine)
• Mice
• Mice, Inbred C57BL
• Middle Aged
• Molecular Weight
• Phenotype
• Polycystic Kidney Diseases (genetics, metabolism, urine)
• Protein Precursors (metabolism, urine)
• Reference Values