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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Mutations causing Greenberg dysplasia but not pelger anomaly uncouple enzymatic from structural functions of a nuclear membrane protein
Nucleus, Volume 1, No. 4, Year 2010
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Description
The lamin B receptor (LBR) is an inner nuclear membrane protein with a structural function interacting with chromatin and lamins, and an enzymatic function as a sterol reductase. Heterozygous LBR mutations cause nuclear hyposegmentation in neutrophils (Pelger anomaly), while homozygous mutations cause prenatal death with skeletal defects and abnormal sterol metabolism (Greenberg dysplasia). It has remained unclear whether the lethality in Greenberg dysplasia is due to cholesterol defects or altered nuclear morphology. To answer this question we characterized two LBR missense mutations and showed that they cause Greenberg dysplasia. Both mutations affect residues that are evolutionary conserved among sterol reductases. In contrast to wildtype LBR, both mutations failed to rescue C14 sterol reductase deficient yeast, indicating an enzymatic defect. We found no Pelger anomaly in the carrier parent excluding marked effects on nuclear structure. We studied Lbr in mouse embryos and demonstrate expression in skin and the developing skeletal system consistent with sites of histological changes in Greenberg dysplasia. Unexpectedly we found in disease-relevant cell types not only nuclear but also cytoplasmatic LBR localization. The cytoplasmatic LBR staining co-localized with ER-markers and is thus consistent with the sites of endogeneous sterol synthesis. We conclude that LBR missense mutations can abolish sterol reductase activity, causing lethal Greenberg dysplasia but not Pelger anomaly. The findings separate the metabolic from the structural function and indicate that the sterol reductase activity is essential for human intrauterine development. © 2010 Landes Bioscience.
Authors & Co-Authors
Clayton, Peter T.
United Kingdom, London
Ucl Great Ormond Street Institute of Child Health
Fischer, Björn
Germany, Berlin
Charité – Universitätsmedizin Berlin
Mansour, Sahar Mahmoud
United Kingdom, London
St George’s, University of London
Rossier, Eva
Germany, Tubingen
Universitätsklinikum Und Medizinische Fakultät Tübingen
Baasanjav, Sevjidmaa
Germany, Leipzig
Universitätsklinikum Leipzig Und Medizinische Fakultät
Germany, Berlin
Charité – Universitätsmedizin Berlin
Demuth, Ilja
Germany, Berlin
Charité – Universitätsmedizin Berlin
Vayá, Amparo
Spain, Valencia
Hospital Universitari I Politècnic la fe
Utermann, Gerd
Unknown Affiliation
Mundlos, Stefan
Germany, Berlin
Charité – Universitätsmedizin Berlin
Germany, Berlin
Max Planck Institute for Molecular Genetics
Stricker, Sigmar
Germany, Berlin
Charité – Universitätsmedizin Berlin
Sperling, Karl
Germany, Berlin
Charité – Universitätsmedizin Berlin
Germany, Berlin
Max Planck Institute for Human Development
Hoffmann, Katrin Katrin
United Kingdom, London
Ucl Great Ormond Street Institute of Child Health
Statistics
Citations: 47
Authors: 12
Affiliations: 9
Identifiers
Doi:
10.4161/nucl.1.4.12435
ISSN:
19491034
Research Areas
Cancer
Genetics And Genomics
Maternal And Child Health
Noncommunicable Diseases