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

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-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
Volume72
Issue number4
DOIs
StatePublished - Apr 1 2003
Externally publishedYes

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Oxidoreductases
Mutation
Moths
Sterols
Granulocytes
Genes
Edema
Fetus
Hydrops Fetalis
Chromatin
Transfection
Sequence Analysis
Exons
Extremities
Complementary DNA
Fibroblasts
Cholesterol
Skin
HEM dysplasia
lamin B receptor

ASJC Scopus subject areas

  • Genetics

Cite this

Autosomal recessive HEM/Greenberg skeletal dysplasia is caused by 3β-hydroxysterol Δ14-reductase deficiency due to mutations in the lamin B receptor gene. / Waterham, Hans R.; Koster, Janet; Mooyer, Petra; Van Noort, Gerard; Kelley, Richard I.; Wilcox, William R.; Wanders, Ronald J A; Hennekam, Raoul C M; Oosterwijk, Jan C.

In: American Journal of Human Genetics, Vol. 72, No. 4, 01.04.2003, p. 1013-1017.

Research output: Contribution to journalArticle

Waterham, HR, Koster, J, Mooyer, P, Van Noort, G, Kelley, RI, Wilcox, WR, Wanders, RJA, Hennekam, RCM & Oosterwijk, JC 2003, 'Autosomal recessive HEM/Greenberg skeletal dysplasia is caused by 3β-hydroxysterol Δ14-reductase deficiency due to mutations in the lamin B receptor gene', American Journal of Human Genetics, vol. 72, no. 4, pp. 1013-1017. https://doi.org/10.1086/373938
Waterham, Hans R. ; Koster, Janet ; Mooyer, Petra ; Van Noort, Gerard ; Kelley, Richard I. ; Wilcox, William R. ; Wanders, Ronald J A ; Hennekam, Raoul C M ; Oosterwijk, Jan C. / Autosomal recessive HEM/Greenberg skeletal dysplasia is caused by 3β-hydroxysterol Δ14-reductase deficiency due to mutations in the lamin B receptor gene. In: American Journal of Human Genetics. 2003 ; Vol. 72, No. 4. pp. 1013-1017.
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