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

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-Huet 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-Huet anomaly represents the heterozygous state of 3beta-hydroxysterol Delta(14)-reductase deficiency.