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A region in the dystrophin gene major hot spot harbors a cluster of deletion breakpoints and generates double-strand breaks in yeast

Manuela Sironi^*,,1, Uberto Pozzoli^*, Giacomo P. Comi, Stefania Riva^*, Andreina Bordoni, Nereo Bresolin^*, and Dilip K. Nag^,

^* Scientific Institute IRCCS E. Medea, Bosisio Parini (LC), Italy;

Molecular Genetics Program, Center for Medical Sciences, Wadsworth Center, Albany, New York, USA;

Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, IRCCS Ospedale Maggiore Policlinico, Mangiagalli and Regina Elena Foundation, Milan, Italy; and

Department of Biomedical Sciences, School of Public Health, State University of New York, Albany, New York, USA

¹Correspondence: IRCCS E. Medea, Via Don L. Monza 20, 23842 Bosisio Parini (LC), Italy. E-mail: msironi{at}bp.lnf.it

ABSTRACT

Deletions within the dystrophin gene (DMD) account for >70% of mutations leading to Duchenne and Becker muscular dystrophies (DMD and BMD). Deletion breakpoints were reported to be scattered within regions that also represent meiotic recombination hot spots. Recent studies indicates that deletion junctions arise from nonhomologous end joining (NHEJ), a major pathway for repairing DNA double-strand breaks (DSBs) in mammals. Here we show that a region in intron 47 (i.e., a major deletion hot spot in the DMD gene) generates DSBs during meiosis in yeast and harbors a cluster of previously sequenced deletion breaks. Mapping of breakpoints in 26 BMD/DMD patients indicated that the frequency of breakpoint occurrence around this region is 3-fold higher than expected by chance. These findings suggest that DSBs mediate deletion formation in intron 47 and possibly account for the high frequency of meiotic recombination in the region. Statistical analysis indicated the presence of at least one other breakpoint cluster in intron 47. Taken together, these results suggest that the primary events in deletion formation occur within discrete regions and that the scattered breakpoint distribution reflects both a variable degree of DSB end processing and the availability of a small (compared to the huge regions involved) deletion junction sample.—Sironi, M., Pozzoli, U., Comi, G. P., Riva, S., Bordoni, A., Bresolin, N., Nag, D. K. A region in the dystrophin gene major hot spot harbors a cluster of deletion breakpoints and generates double-strand breaks in yeast.