A CTG polymorphism in the CNDP1 gene determines the secretion of serum carnosinase in Cos-7 transfected cells.
Recently, we demonstrated that a polymorphism in exon 2 of the serum carnosinase (CNDP1) gene is associated with susceptibility to developing diabetic nephropathy. Based on the number of CTG repeats in the signal peptide, five different alleles coding for 4, 5, 6, 7, or 8 leucines (4L-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 five leucines in the signal peptide. Hence, our data might explain why individuals homozygous for the 5L allele have low serum carnosinase activity. Because carnosine, the natural substrate for carnosinase, exerts antioxidative effects and inhibits ACE activity and advanced glycation end product formation, our results support the finding that diabetic patients homozygous for CNDP1 5L are protected against diabetic nephropathy.
Riedl
Eva
E
Department of Nephrology, Endocrinology, and Rheumatology, Fifth Medical Clinic, Mannheim, Germany.
Koeppel
Hannes
H
Brinkkoetter
Paul
P
Sternik
Paula
P
Steinbeisser
Herbert
H
Sauerhoefer
Sibylle
S
Janssen
Bart
B
van der Woude
Fokko J
FJ
Yard
Benito A
BA
D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D003928:Diabetic Nephropathies / Q000235:genetics; D004150:Dipeptidases / Q000097:blood* / Q000235:genetics*; D005091:Exons; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D000882:Haplorhini; D006801:Humans; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D014162:Transfection
C522928:CNDP1 protein, human; D004150:Dipeptidases; C019673:aminoacyl-histidine dipeptidase