Medical & Clinical Research

Author(s): Paola Cattelan, Daniela Segat, Maria Vittoria Enzo, Uros Hladnik and Paola de Gemmis*

Background: Lesch-Nyhan disease (LND) is an X-linked rare pathology involving the purine nucleotides salvage pathway. Its incidence is estimated in 1:350.000 born. The condition is due to mutations in the HPRT1 (hypoxanthine phosphoribosyl transferase 1) gene of which in our cohort 28% (10/35) are large deletions. In order to better assess the nature of the observed deletions in our LND population we analyzed 10 families carrying large deletions in the HPRT1 gene region and studied the underlying pathogenic mechanisms.

Methods: We performed PCR based localization of the break points and sequenced the gap-junction fragments. Bioinformatics analysis was performed through several web tools on the 5’ and 3’ break points to determine the factors involved in the deletion mechanism.

Results: We precisely mapped 10 unique large deletions involving the HPRT1 gene region that span from 300 bp to 64 kbp. No common breakpoints were found and each deletion appears to be family specific.

Conclusions: The deletions in the HPRT1 gene area are consistent with the Micro homology-Mediated Break-Induced Replication (MMBIR) mechanism. There are strong links with Alu-s and no recurrent break points with all of the observed deletions being unique. The relatively large amount of deletions in the HPRT1 region is peculiar and linked with the almost absolute lack of polymorphic sites in the HPRT1 gene making it a very interesting region for further studies.