Gene conversion is a likely cause of mutation in PKD1

Approximately 70% of the gene responsible for the most common form ofautosomal dominant polycystic kidney disease ( PKD1 ) is replicated inseveral highly homologous copies located more proximally on chromosome 16.We recently have described a novel technique for mutation detection in theduplicated region of PKD1 that circumvents the difficulties posed by thesehomologs. We have used this method to identify two patients with a nearlyidentical cluster of base pair substitutions in exon 23. Since pseudogenesare known to be reservoirs for mutation via gene conversion events for anumber of other diseases, we decided to test whether these sequencedifferences in PKD1 could have arisen as a result of this mechanism. Usingchanges in restriction digest patterns, we were able to show that thesesequence substitutions are also present in N23HA, a rodent-human somaticcell hybrid that contains only the PKD1 homologs. Moreover, these changeswere also detected in total DNA from several affected and unaffectedindividuals that did not harbor this mutation in their PKD1 gene copy. Thisis the first example of gene conversion in PKD1 , and our findingshighlight the importance of using gene-specific reagents in defining PKD1mutations.