Mutations in the gene encoding 3β-hydroxysteroid-Δ⁸,Δ⁷-isomerase cause X-linked dominant Conradi-Hunermann syndrome

X-linked dominant Conradi-Hunermann 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 (ref. 4). This pattern of accumulated cholesterol intermediates suggested a deficiency of 3β-hydroxysteroid- Δ⁸,Δ⁷-isomerase (sterol-Δ⁸-isomerase), which catalyses an intermediate step in the conversion of lanosterol to cholesterol. A candidate gene encoding a sterol-Δ⁸-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-Δ⁸- isomerase-deficient yeast strain. Our results indicate that defects in sterol-Δ⁸-isomerase cause CDPX2 and suggest a role for sterols in bone development.