Mutations in the gene encoding 3β- hydroxysteroid-Δ87- isomerase cause X-linked dominant Conradi-Hünermann syndrome


X-linked dominant Conradi-Hünermann 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 atrophoderma1. 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 reported2,3. 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-Δ87-isomerase (sterol-Δ8-isomerase), which catalyses an intermediate step in the conversion of lanosterol to cholesterol4. 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.

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Figure 1: Sterol metabolism in CPDX2.
Figure 2: Heterozygous mutations in EBP in all seven probands.
Figure 3: GC flame ionization profile of sterols extracted from the erg2-3 strain transformed with vector alone (a), wild-type human EBP (b), human EBP containing the E80K mutation ( c) and human EBP containing the R147H mutation (d).
Figure 4: Sterol-Δ8-isomerase mutant proteins are stable.

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We thank the International Skeletal Dysplasia Registry for tissue donations by L. Raffel, A. Soffici, M. Bendon and D. Agamanolis, and G. Nyakatura for providing the DNA sequence of cosmid clone LLNc110A0842 and S. Muscelli for assistance with preparation of this manuscript. This work was supported in part by a NIH grant to the Kennedy Krieger Institute (PO1HD10981, D.V.) and to the General Clinical Research Centers (RR00052 and RR00722, N.B.) and Human Frontiers Sciences Project (F.F.M.), Fonds zur förderung der wissenschaftlichen Forschung (P11636 (HG)) and the Oesterreische Nationalbank (P6515 (HG)). D.V. is an Investigator in the Howard Hughes Medical Institute.

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Braverman, N., Lin, P., Moebius, F. et al. Mutations in the gene encoding 3β- hydroxysteroid-Δ87- isomerase cause X-linked dominant Conradi-Hünermann syndrome. Nat Genet 22, 291–294 (1999).

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