Mutational analysis of the SOX9 gene in campomelic dysplasia and autosomal sex reversal: lack of genotype/phenotype correlations

It has previously been shown that, in the heterozygous state, mutations inthe SOX9 gene cause campomelic dysplasia (CD) and the often associatedautosomal XY sex reversal. In 12 CD patients, 10 novel mutations and onerecurrent mutation were characterized in one SOX9 allele each, and in onecase, no mutation was found. Four missense mutations are all located withinthe high mobility group (HMG) domain. They either reduce or abolish theDNA-binding ability of the mutant SOX9 proteins. Among the five nonsenseand three frameshift mutations identified, two leave the C-terminaltransactivation (TA) domain encompassing residues 402-509 of SOX9 partly oralmost completely intact. When tested in cell transfection experiments, therecurrent nonsense mutation Y440X, found in two patients who survived forfour and more than 9 years, respectively, exhibits some residualtransactivation ability. In contrast, a frameshift mutation extending theprotein by 70 residues at codon 507, found in a patient who died shortlyafter birth, showed no transactivation. This is apparently due toinstability of the mutant SOX9 protein as demonstrated by Western blotting.Amino acid substitutions and nonsense mutations are found in patients withand without XY sex reversal, indicating that sex reversal in CD is subjectto variable penetrance. Finally, none of 18 female patients with XY gonadaldysgenesis (Swyer syndrome) showed an altered SOX9 banding pattern in SSCPassays, providing evidence that SOX9 mutations do not usually result in XYsex reversal without skeletal malformations.