title: Autosomal recessive HEM/Greenberg skeletal dysplasia is caused by 3 beta-hydroxysterol delta 14-reductase deficiency due to mutations in the lamin B receptor gene.
abstract: Hydrops-ectopic calcification-"moth-eaten" (HEM) or Greenberg skeletal dysplasia is an autosomal recessive chondrodystrophy with a lethal course, characterized by fetal hydrops, short limbs, and abnormal chondro-osseous calcification. We found elevated levels of cholesta-8,14-dien-3beta-ol in cultured skin fibroblasts of an 18-wk-old fetus with HEM, compatible with a deficiency of the cholesterol biosynthetic enzyme 3beta-hydroxysterol delta(14)-reductase. Sequence analysis of two candidate genes encoding putative human sterol delta(14)-reductases (TM7SF2 and LBR) identified a homozygous 1599-1605TCTTCTA-->CTAGAAG substitution in exon 13 of the LBR gene encoding the lamin B receptor, which results in a truncated protein. Functional complementation of the HEM cells by transfection with control LBR cDNA confirmed that LBR encoded the defective sterol delta(14)-reductase. Mutations in LBR recently have been reported also to cause Pelger-Huët anomaly, an autosomal dominant trait characterized by hypolobulated nuclei and abnormal chromatin structure in granulocytes. The fact that the healthy mother of the fetus showed hypolobulated nuclei in 60% of her granulocytes confirms that classic Pelger-Huët anomaly represents the heterozygous state of 3beta-hydroxysterol delta(14)-reductase deficiency.
authors.affiliation: Department of Pediatrics, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands. h.r.waterham@amc.uva.nl
authors.forename: Hans R
authors.initials: HR
authors.lastname: Waterham
authors.forename: Janet
authors.initials: J
authors.lastname: Koster
authors.forename: Petra
authors.initials: P
authors.lastname: Mooyer
authors.forename: Gerard van
authors.initials: Gv
authors.lastname: Noort Gv
authors.forename: Richard I
authors.initials: RI
authors.lastname: Kelley
authors.forename: William R
authors.initials: WR
authors.lastname: Wilcox
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.forename: Raoul C M
authors.initials: RC
authors.lastname: Hennekam
authors.forename: Jan C
authors.initials: JC
authors.lastname: Oosterwijk
mesh_terms: D001483:Base Sequence; D001847:Bone Diseases / Q000235:genetics* / Q000473:pathology; D002784:Cholesterol / Q000096:biosynthesis; D017931:DNA Primers; D005808:Genes, Recessive; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010088:Oxidoreductases / Q000172:deficiency / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D017422:Sequence Analysis, DNA; D000097682:Lamin B Receptor
chemical_list: D002784:Cholesterol; D017931:DNA Primers; D010088:Oxidoreductases; D018160:Receptors, Cytoplasmic and Nuclear; D000097682:Lamin B Receptor; C022672:delta(14)-sterol reductase