title: Mutations in the gene encoding 3 beta-hydroxysteroid-delta 8, delta 7-isomerase cause X-linked dominant Conradi-Hünermann syndrome.
abstract: 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 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 3beta-hydroxysteroid-delta8,delta7-isomerase (sterol-delta8-isomerase), which catalyses an intermediate step in the conversion of lanosterol to cholesterol. A candidate gene encoding a sterol-delta8-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-delta8-isomerase-deficient yeast strain. Our results indicate that defects in sterol-delta8-isomerase cause CDPX2 and suggest a role for sterols in bone development.
authors.affiliation: Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: N
authors.initials: N
authors.lastname: Braverman
authors.forename: P
authors.initials: P
authors.lastname: Lin
authors.forename: F F
authors.initials: FF
authors.lastname: Moebius
authors.forename: C
authors.initials: C
authors.lastname: Obie
authors.forename: A
authors.initials: A
authors.lastname: Moser
authors.forename: H
authors.initials: H
authors.lastname: Glossmann
authors.forename: W R
authors.initials: WR
authors.lastname: Wilcox
authors.forename: D L
authors.initials: DL
authors.lastname: Rimoin
authors.forename: M
authors.initials: M
authors.lastname: Smith
authors.forename: L
authors.initials: L
authors.lastname: Kratz
authors.forename: R I
authors.initials: RI
authors.lastname: Kelley
authors.forename: D
authors.initials: D
authors.lastname: Valle
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D002806:Chondrodysplasia Punctata / Q000201:enzymology* / Q000235:genetics*; D004247:DNA / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D007231:Infant, Newborn; D008969:Molecular Sequence Data; D009154:Mutation; D011247:Pregnancy; D013251:Steroid Isomerases / Q000235:genetics*; D014960:X Chromosome / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D017931:DNA Primers; D004247:DNA; D013251:Steroid Isomerases; C022669:delta(8)-delta(7)-sterol isomerase; C090445:EBP protein, human