A TRANSLATION FRAMESHIFT MUTATION INDUCED BY A CYTOSINE INSERTION IN THE POLYCYSTIC-KIDNEY-DISEASE-2 GENE (PKD2)

Mutations in the PKD2 gene on the long arm of chromosome 4 are respons ible for similar to 15% of cases of polycystic kidney disease, Perhaps the only difference from the more common ADPKD1 cases is the rate of progression of cystic changes, and the age of onset, which is 10-15 ye ars later for the ADPKD2 form, In Cyprus there are at least three larg e families, documented by molecular linkage analysis, that map to the PKD2 locus, For two of them the defects were recently shown to be nons ense mutations at positions arginine 742 and glutamine 405. In this re port, we describe the mutation in the third family, CY1602. For this, the entire coding sequence was systematically screened by single stran d conformation analysis and heteroduplex formation, A novel mutation w as identified in exon 2 where a new cytosine residue was inserted imme diately after codon 231 (231insC). It causes a translation frameshift and is expected to lead to the introduction of 37 novel amino acids be fore the translation reaches a new STOP codon, It is the most amino te rminal mutation reported to date, and based on the protein's modeled s tructure, is predicted to be within the first transmembrane domain, It is the fourth PKD2 mutation reported thus far, and the first which is not a nonsense mutation.