Skip Navigation


Human Molecular Genetics Advance Access originally published online on April 2, 2007
Human Molecular Genetics 2007 16(10):1176-1187; doi:10.1093/hmg/ddm065
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Supplementary Data
Right arrow All Versions of this Article:
16/10/1176    most recent
ddm065v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (3)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Wassif, C. A.
Right arrow Articles by Porter, F. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wassif, C. A.
Right arrow Articles by Porter, F. D.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Published by Oxford University Press 2007. For Permissions, please email: journals.permissions@oxfordjournals.org

HEM dysplasia and ichthyosis are likely laminopathies and not due to 3ß-hydroxysterol {Delta}14-reductase deficiency

Christopher A. Wassif1, Kirstyn E. Brownson1, Allison L. Sterner1, Antonella Forlino3, Patricia M. Zerfas2, William K. Wilson4, Matthew F. Starost2 and Forbes D. Porter1,*

1 Heritable Disorders Branch, NICHD and 2 Diagnostic and Research Services Branch, OD, NIH, DHHS, Bethesda, MD 20892, USA 3 Department of Biochemistry, Section of Medicine and Pharmacy, University of Pavia, Italy 4 Department of Biochemistry and Cell Biology, Rice University, Houston, TX 77005, USA

* To whom correspondence should be addressed at: HDB, NICHD, NIH, DHHS Bld. 10, Room 9D42 10 Center Dr, Bethesda, MD 20892-1830, USA. Tel: +1 3014354432; Fax: +1 3014805791; Email: fdporter{at}mail.nih.gov

Received January 30, 2007; Revised March 5, 2007; Accepted March 13, 2007

Mutations of the lamin B receptor (LBR) have been shown to cause HEM dysplasia in humans and ichthyosis in mice. LBR is a bifunctional protein with both a lamin B binding and a sterol {Delta}14-reductase domain. It previously has been proposed that LBR is the primary sterol {Delta}14-reductase and that HEM dysplasia and ichthyosis are inborn errors of cholesterol synthesis. However, DHCR14 also encodes a sterol {Delta}14-reductase and could provide enzymatic redundancy with respect to cholesterol synthesis. To test the hypothesis that LBR and DHCR14 both function as sterol {Delta}14-reductases, we obtained ichthyosis mice (Lbr–/–) and disrupted Dhcr14. Heterozygous Lbr and Dhcr14 mice were intercrossed to test for a digenic phenotype. Lbr–/–, Dhcr14{Delta}4-7/{Delta}4-7 and Lbr+/–:Dhcr14{Delta}4-7/{Delta}4-7 mutant mice have distinct physical and biochemical phenotypes. Dhcr14{Delta}4-7/{Delta}4-7 mice are essentially normal, whereas Lbr+/–:Dhcr14{Delta}4-7/{Delta}4-7 mice are growth retarded and neurologically abnormal. Neither of these mutants resembles the ichthyosis mouse and biochemically, no sterol abnormalities were detected in either liver or kidney tissue. In contrast, relatively small transient elevations of {Delta}14-sterols were observed in Lbr–/– and Dhcr14{Delta}4-7/{Delta}4-7 brain tissue, and marked elevations were seen in Lbr+/–:Dhcr14{Delta}4-7/{Delta}4-7 brain. Pathological evaluation demonstrated vacuolation and swelling of the myelin sheaths in the spinal cord of Lbr+/–:Dhcr14{Delta}4-7/{Delta}4-7 mice consistent with a demyelinating process. This was not observed in either Lbr–/– or Dhcr14 {Delta}4-7/{Delta}4-7 mice. Our data support the conclusions that LBR and DHCR14 provide substantial enzymatic redundancy with respect to cholesterol synthesis and that HEM dysplasia and ichthyosis are laminopathies rather than inborn errors of cholesterol synthesis.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Hum Mol GenetHome page
T. V. Cohen, K. D. Klarmann, K. Sakchaisri, J. P. Cooper, D. Kuhns, M. Anver, P. F. Johnson, S. C. Williams, J. R. Keller, and C. L. Stewart
The lamin B receptor under transcriptional control of C/EBP{varepsilon} is required for morphological but not functional maturation of neutrophils
Hum. Mol. Genet., October 1, 2008; 17(19): 2921 - 2933.
[Abstract] [Full Text] [PDF]

Home page
 J BiochemHome page
Y. Tsuchiya
Till Disassembly Do Us Part: A Happy Marriage of Nuclear Envelope and Chromatin
J. Biochem., February 1, 2008; 143(2): 155 - 161.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.