A NOVEL NONSENSE MUTATION IN THE PKD1 GENE (C3817T) IS ASSOCIATED WITH AUTOSOMAL-DOMINANT POLYCYSTIC KIDNEY-DISEASE (ADPKD) IN A LARGE 3-GENERATION ITALIAN FAMILY

We have looked for disease-causing mutations in the PKD1 gene in 20 un related ADPKD probands from northern Italy, all members of families in which our previous studies had indicated linkage to PKD1, Using PCR w ith primer pairs located in the 3' unique region of the gene and heter oduplex DNA analysis, we have detected novel aberrant bands in five af fected individuals from the same family, which were absent in 13 other unaffected family members, Cloning and automated DNA sequencing revea led a C to T transition at nucleotide position 3817 of the published c DNA sequence, which created a premature stop codon, The mutation destr oyed a MspA1l restriction site, and the abnormal restriction pattern w as observed on genomic DNA from all the affected family members, RT-PC R and restriction analysis performed on peripheral white blood cell mR NA showed that in the affected members, both the mutant and the normal transcript are represented, This mutation was not found in the proban ds of the other families studied, To our knowledge, this is the first nonsense mutation described in the PKD1 gene.