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

Am J Hum Genet. 2003 Apr;72(4):1013-7. doi: 10.1086/373938. Epub 2003 Feb 28.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Bone Diseases / genetics*
  • Bone Diseases / pathology
  • Cholesterol / biosynthesis
  • DNA Primers
  • Genes, Recessive*
  • Humans
  • Molecular Sequence Data
  • Mutation*
  • Oxidoreductases / deficiency
  • Oxidoreductases / genetics*
  • Receptors, Cytoplasmic and Nuclear / genetics*
  • Sequence Analysis, DNA

Substances

  • DNA Primers
  • Receptors, Cytoplasmic and Nuclear
  • lamin B receptor
  • Cholesterol
  • Oxidoreductases
  • delta(14)-sterol reductase

Associated data

  • GENBANK/AF096303
  • GENBANK/L25931
  • GENBANK/L25932
  • GENBANK/L25933
  • GENBANK/L25934
  • GENBANK/L25935
  • GENBANK/L25936
  • GENBANK/L25937
  • GENBANK/L25938
  • GENBANK/L25939
  • GENBANK/L25940
  • GENBANK/L25941