A novel nonsense mutation in the PKD1 gene (C3817T) is associated with autosomal dominant polycystic kidney disease (ADPKD) in a large three-generation Italian family.

We have looked for disease-causing mutations in the PKD1 gene in 20 unrelated ADPKD probands from northern Italy, all members of families in which our previous studies had indicated linkage to PKD1. Using PCR with primer pairs located in the 3' unique region of the gene and heteroduplex DNA analysis, we have detected novel aberrant bands in five affected individuals from the same family, which were absent in 13 other unaffected family members. Cloning and automated DNA sequencing revealed a C to T transition at nucleotide position 3817 of the published cDNA sequence, which created a premature stop codon. The mutation destroyed a MspA1I restriction site, and the abnormal restriction pattern was observed on genomic DNA from all the affected family members. RT-PCR and restriction analysis performed on peripheral white blood cell mRNA showed that in the affected members, both the mutant and the normal transcript are represented. This mutation was not found in the probands of the other families studied. To our knowledge, this is the first nonsense mutation described in the PKD1 gene.