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-Δ8,Δ7-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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Happle, R. X-linked dominant chondrodysplasia punctata. Review of literature and report of a case. Hum. Genet. 53, 65– 73 (1979).
Happle, R. X-linked dominant chondrodysplasia punctata/ichthyosis/cataract syndrome in males. Am. J. Med. Genet. 57, 493 (1995).
Sutphen, R., Amar, M.J., Kousseff, B.G. & Toomey, K.E. XXY male with X-linked dominant chondrodysplasia punctata (Happle syndrome). Am. J. Med. Genet. 57, 489– 492 (1995).
Kelley, R.I. et al. Abnormal sterol metabolism in patients with Conradi-Hunermann-Happle syndrome and sporadic lethal chondrodysplasia punctata. Am. J. Med. Genet. 83, 213–219 (1999).
Hanner, M. et al. Phenylalkylamine Ca2+ antagonist binding protein. Molecular cloning, tissue distribution, and heterologous expression. J. Biol. Chem. 270, 7551–7557 (1995).
Schindelhauer, D. et al. Long-range map of a 3.5-Mb region in Xp11.23-22 with a sequence-ready map from a 1.1-Mb gene-rich interval. Genome Res. 6 , 1056–1069 (1996).
Tint, G.S. et al. Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome. N. Engl. J. Med. 330, 107– 113 (1994).
Fitzky, B.U. et al. Mutations in the Δ7-sterol reductase gene in patients with the Smith-Lemli-Opitz syndrome. Proc. Natl Acad. Sci USA 95, 8181–8186 (1998).
Bjorkhem, I. et al. Correlation between serum levels of cholesterol precursors and activity of HMG-CoA reductase in human liver. J. Lipid Res. 28, 1137–1143 ( 1987).
Moebius, F.F. et al. Purification and amino-terminal sequencing of the high affinity phenylalkylamine Ca2+ antagonist binding protein from guinea pig liver endoplasmic reticulum. J. Biol. Chem. 269 , 29314–29320 (1994).
Silve, S. et al. Emopamil-binding protein, a mammalian protein that binds a series of structurally diverse neuroprotective agents, exhibits Δ8-Δ7 sterol isomerase activity in yeast. J. Biol. Chem. 271, 22434–22440 (1996).
Moebius, F.F. et al. Histidine77, glutamic acid81, glutamic acid123, threonine126, asparagine194, and tryptophan197 of the human emopamil binding protein are required for in vivo sterol Δ8-Δ7 isomerization. Biochemistry 38, 1119–1127 (1999).
Ashman, W.H., Barbuch, R.J., Ulbright, C.E., Jarrett, H.W. & Bard, M. Cloning and disruption of the yeast C-8 sterol isomerase gene. Lipids 26, 628 –632 (1991).
Herman, G.E. & Walton, S.J. Close linkage of the murine locus bare patches to the X-linked visual pigment gene: implications for mapping human X-linked dominant chondrodysplasia punctata. Genomics 7, 307–312 (1990).
Herman, G.E. et al. The gene mutated in bare patches and striated mice encodes a novel 3β-hydroxysteroid dehydrodenase. Nature Genet. 22, 182–187 (1999).
FitzPatrick, D.R. et al. Clinical phenotype of desmosterolosis. Am. J. Med. Genet. 75, 145–152 (1998).
Cooper, M.K., Porter, J.A., Young, K.E. & Beachy, P.A. Teratogen-mediated inhibition of target tissue response to Shh signaling. Science 280, 1603–1607 (1998).
Porter, J.A., Young, K.E. & Beachy, P.A. Cholesterol modification of hedgehog signaling proteins in animal development. Science 274, 255– 259 (1996).
Karaplis, A.C. et al. Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene. Genes Dev. 8, 277–289 (1994).
Lanske, B. et al. PTH/PTHrP receptor in early development and Indian hedgehog-regulated bone growth. Science 273, 663– 666 (1996).
Chuang, P.T. & McMahon, A.P. Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature 397, 617–621 (1999).
Derry, J.M.J et al. Mutations in a Δ8-Δ7 sterol isomerase in the tattered mouse and X-linked dominant chondrodysplasia punctata Nature Genet. 22, 286- 293 (1999).
Kelley, R.I. Diagnosis of Smith-Lemli-Opitz syndrome by gas chromatography/mass spectrometry of 7-dehydrocholesterol in plasma, amniotic fluid and cultured skin fibroblasts. Clin. Chim. Acta 236, 45– 58 (1995).
Brody, L.C. et al. Ornithine-δ-aminotransferase mutations causing gyrate atrophy: allelic heterogeneity and functional consequences. J. Biol. Chem. 267, 3302–3307 (1992).
Braverman, N. et al. Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata. Nature Genet. 15, 369–376 ( 1997).
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-Δ8,Δ7- isomerase cause X-linked dominant Conradi-Hünermann syndrome. Nat Genet 22, 291–294 (1999). https://doi.org/10.1038/10357
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