Mutations in the gene encoding 3 beta-hydroxysteroid-Delta(8),Delta(7)-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 vertebra l column, pelvis and long bones in CPDX2. Additionally, CDPX2 patients may have asymmetric rhizomesomelia, sectorial cataracts, patchy alopecia, ichth yosis and atrophoderma(1). The phenotype in CDPX2 females ranges from still born to mildly affected individuals identified in adulthood. CDPX2 is presu med lethal in males, although a few affected males have been reported(2,3). We found increased 8(9)-cholestenol and 8-dehydrocholesterol in tissue sam ples from seven female probands with CDPX2 (ref. 4). This pattern of accumu lated cholesterol intermediates suggested a deficiency of 3 beta-hydroxyste roid-Delta(8),Delta(7)-isomerase (sterol-Delta(8)-isomerase), which catalys es an intermediate step in the conversion of lanosterol to cholesterol(4). A candidate gene encoding a sterol-Delta(8)-isomerase (EBP) has been identi fied and mapped to Xp11.22-p11.23 (refs 5,6). Using SSCP analysis and seque ncing 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(8)-isomerase-deficient yeast strain. Our results indicate tha t defects in sterol-Delta(8)-isomerase cause CDPX2 and suggest a role for s terols in bone development.