GENE CONVERSION IS A LIKELY CAUSE OF MUTATION IN PKD1

Approximately 70% of the gene responsible for the most common form of autosomal dominant polycystic kidney disease (PKD1) is replicated in s everal highly homologous copies located more proximally on chromosome 16, We recently have described a novel technique for mutation detectio n in the duplicated region of PKD1 that circumvents the difficulties p osed by these homologs, We have used this method to identify two patie nts with a nearly identical cluster of base pair substitutions in exon 23, Since pseudogenes are known to be reservoirs for mutation via gen e conversion events for a number of other diseases, we decided to test whether these sequence differences in PKD1 could have arisen as a res ult of this mechanism. Using changes in restriction digest patterns, w e were able to show that these sequence substitutions are also present in N23HA, a rodent-human somatic cell hybrid that contains only the P KD1 homologs, Moreover, these changes were also detected in total DNA from several affected and unaffected individuals that did not harbor t his mutation in their PKD1 gene copy, This is the first example of gen e conversion in PKD1, and our findings highlight the importance of usi ng gene-specific reagents in defining PKD1 mutations.