Mutations in the gene encoding 3 beta -hydroxysteroid- Delta super(8), Delta super(7)-isomerase cause X-linked dominant Conradi-Huenermann syndrome

X-linked dominant Conradi-Huenermann syndrome (CDPX2; MIM 302960) is one of a group of disorders with aberrant punctate calcification in cartilage, or chondrodysplasia punctata (CDP). This is most prominent around the vertebral column, pelvis and long bones in CPDX2. Additionally, CDPX2 patients may have asymmetric rhizomesomelia, sectorial cataracts, patchy alopecia, ichthyosis and atrophoderma. The phenotype in CDPX2 females ranges from stillborn to mildly affected individuals identified in adulthood. CDPX2 is presumed lethal in males, although a few affected males have been reported. We found increased 8(9)-cholestenol and 8-dehydrocholesterol in tissue samples from seven female probands with CDPX2. This pattern of accumulated cholesterol intermediates suggested a deficiency of 3 beta -hydroxysteroid- Delta super(8), Delta super(7)-isomerase (sterol- Delta super(8)-isomerase), which catalyses an intermediate step in the conversion of lanosterol to cholesterol. A candidate gene encoding a sterol- Delta super(8)-isomerase (EBP) has been identified and mapped to Xp11.22-p11.23 (refs 5,6). Using SSCP analysis and sequencing of genomic DNA, we found EBP mutations in all probands. We confirmed the functional significance of two missense alleles by expressing them in a sterol- Delta super(8)-isomerase-deficient yeast strain. Our results indicate that defects in sterol- Delta super(8)-isomerase cause CDPX2 and suggest a role for sterols in bone development.