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A CTG Polymorphism in the CNDP1 gene determines the secretion of serum carnosinase in Cos-7 transfected cells.

¹ Department of Nephrology, Endocrinology and Rheumatology, Fifth Medical Clinic, Mannheim, Germany
² Institute of Human Genetics Heidelberg, Heidelberg, Germany

Correspondence: hannes.koeppel{at}med5.ma.uni-heidelberg.de

Recently, we demonstrated that a polymorphism in exon 2 of the serum carnosinase (CNDP1) gene is associated with susceptibility to develop diabetic nephropathy. Based on the number of CTG repeats in the signal peptide, 5 different alleles coding for 4, 5, 6, 7 or 8 leucines (4L to 8L) are known. Diabetic patients without nephropathy are homozygous for the 5L allele more frequently than those with nephropathy. Since serum carnosinase activity correlates with CNDP1 genotype, we hypothesized in the present study that secretion of serum carnosinase is determined by the CNDP1 genotype. To test this hypothesis, we transfected COS-7 cells with different CNDP1 constructs varying in CTG repeats and assessed the expression of CNDP1 protein in cell extracts and supernatants. Our results demonstrate that CNDP1 secretion is significantly higher in cells expressing variants with more than 5 leucines in the signal peptide. Hence, our data might explain why individuals homozygous for 5L have low serum carnosinase activity. Because carnosine, the natural substrate for carnosinase, exerts anti-oxidative effects, inhibits ACE activity and AGE formation, our results support the finding that diabetic patients homozygous for CNDP1 5L are protected against DN.

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