Autosomal recessive HEM/Greenberg skeletal dysplasia is caused by 3β-hydroxysterol Δ14-reductase deficiency due to mutations in the lamin B receptor gene

Hans R. Waterham, Janet Koster, Petra Mooyer, Gerard Van Noort, Richard I. Kelley, William R. Wilcox, Ronald J.A. Wanders, Raoul C.M. Hennekam, Jan C. Oosterwijk

Research output: Contribution to journalArticle


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-3β-ol in cultured skin fibroblasts of an 18-wk-old fetus with HEM, compatible with a deficiency of the cholesterol biosynthetic enzyme 3β-hydroxysterol Δ14-reductase. Sequence analysis of two candidate genes encoding putative human sterol Δ14-reductases (TM7SF2 and LBR) identified a homozygous 1599-1605TCTTCTAC→TAGAAG 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 Δ14-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 3β-hydroxysterol Δ14-reductase deficiency.

Original languageEnglish (US)
Pages (from-to)1013-1017
Number of pages5
JournalAmerican journal of human genetics
Issue number4
StatePublished - Apr 1 2003

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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