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  Mutations causing Greenberg dysplasia but not Pelger anomaly uncouple enzymatic from structural functions of a nuclear membrane protein.

Clayton, P., Fischer, B., Mann, A., Mansour, S., Rossier, E., Veen, M., et al. (2010). Mutations causing Greenberg dysplasia but not Pelger anomaly uncouple enzymatic from structural functions of a nuclear membrane protein. Nucleus, 1(4), 354-366. doi:10.4161/nucl.1.4.12435.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-7B07-A Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-7B08-8
Genre: Journal Article
Alternative Title : Nucleus

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 Creators:
Clayton, P., Author
Fischer, B., Author
Mann, A., Author
Mansour, S., Author
Rossier, E., Author
Veen, M., Author
Lang, C., Author
Baasanjav, S., Author
Kieslich, M., Author
Brossuleit, K., Author
Gravemann, S., Author
Schnipper, N., Author
Karbasyian, M., Author
Demuth, I., Author
Zwerger, M., Author
Vaya, A., Author
Utermann, G., Author
Mundlos, S.1, Author              
Stricker, S.1, Author              
Sperling, K., Author
Hoffmann, K.1, Author               more..
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              

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Free keywords: Greenberg dysplasia; Pelger anomaly; lamin B receptor; sterol-metabolism; C14 sterol reductase
 Abstract: 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.

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Language(s): eng - English
 Dates: 2010-05-21
 Publication Status: Published in print
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Title: Nucleus
  Alternative Title : Nucleus
Source Genre: Journal
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Pages: - Volume / Issue: 1 (4) Sequence Number: - Start / End Page: 354 - 366 Identifier: ISSN: 1949-1034