DOUBLE-STRAND BREAKS MAY INITIATE THE INVERSION MUTATION CAUSING THE HUNTER SYNDROME

We have previously shown that patients with the Hunter syndrome freque ntly have suffered from a recombination event between the IDS gene and its putative pseudogene, IDS-2, resulting in an inversion of the inte rvening DNA. The inversion, which might be the consequence of an intra chromosomal mispairing, is caused by homologous recombination between sequences located in intron 7 of the IDS gene and sequences located di stal of exon 3 in IDS-2, In order to gain insight into the mechanisms causing the inversion, we have isolated both inversion junctions in si x unrelated patients, DNA sequence analysis of the junctions showed th at all recombinations have taken place within al kb region where the s equence identity is >98%, An interesting finding was the identificatio n of regions with alternating IDS gene and IDS-2 sequences present at one inversion junction, suggesting that the recombination event has be en initiated by a double-strand break in intron 7 of the IDS gene, The results from this study suggest that homologous recombination in man could be explained by mechanisms similar to those described for Saccha romyces cerevisiae. The results also have practical implications for d iagnosis of patients with the Hunter syndrome.