MUTATIONS IN SOX9, THE GENE RESPONSIBLE FOR CAMPOMELIC DYSPLASIA AND AUTOSOMAL SEX REVERSAL

Campomelic dysplasia (CD) is a skeletal malformation syndrome frequent ly accompanied by 46,XY sex reversal. A mutation-screening strategy us ing SSCP was employed to identify mutations in SOX9, the chromosome 17 q24 gene responsible for CD and autosomal sex reversal in man. We have screened seven CD patients with no cytologically detectable chromosom al aberrations and two CD patients with chromosome 17 rearrangements f or mutations in the entire open reading frame of SOX9. Five different mutations have been identified in six CD patients: two missense mutati ons in the SOX9 putative DNA binding domain (high mobility group, or H MG, box); three frameshift mutations and a splice-acceptor mutation. A n identical frameshift mutation is found in two unrelated 46,XY patien ts, one exhibiting a male phenotype and the other displaying a female phenotype (XY sex reversal). All mutations found affect a single allel e, which is consistent with a dominant mode of inheritance. No mutatio ns were found in the SOX9 open reading frame of two patients with chro mosome 17q rearrangements, suggesting that the translocations affect S OX9 expression. These findings are consistent with the hypothesis that CD results from haploinsufficiency of SOX9.