DELETION OF LONG-RANGE REGULATORY ELEMENTS UPSTREAM OF SOX9 CAUSES CAMPOMELIC DYSPLASIA

Campomelic dysplasia (CD) is a rare, neonatal human chondrodysplasia c haracterized by bowing of the long bones and often associated with mal e-to-female sex-reversal. Patients present with either heterozygous mu tations in the SOX9 gene or chromosome rearrangements mapping at least 50 kb upstream of SOX9. Whereas mutations in SOX9 ORF cause haploinsu fficiency, the effects of translocations 5' to SOX9 are unclear. To te st whether these rearrangements also cause haploinsufficiency by alter ing spatial and temporal expression of SOX9, we generated mice transge nic for human SOX9-lacZ yeast artificial chromosomes containing variab le amounts of DNA sequences upstream of SOX9. We show that elements ne cessary for SOX9 expression during skeletal development are highly con served between mouse and human and reveal that a rearrangement upstrea m of SOX9, similar to those observed in CD patients,leads to a substan tial reduction of SOX9 expression, particularly in chondrogenic tissue s. These data demonstrate that important regulatory elements are scatt ered over a large region upstream of SOX9 and explain how particular a spects of the CD phenotype are caused by chromosomal rearrangements 5' to SOX9.