Journal Article

HEM dysplasia and ichthyosis are likely laminopathies and not due to 3β-hydroxysterol Δ<sup>14</sup>-reductase deficiency

Christopher A. Wassif, Kirstyn E. Brownson, Allison L. Sterner, Antonella Forlino, Patricia M. Zerfas, William K. Wilson, Matthew F. Starost and Forbes D. Porter

in Human Molecular Genetics

Volume 16, issue 10, pages 1176-1187
Published in print May 2007 | ISSN: 0964-6906
Published online April 2007 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddm065
HEM dysplasia and ichthyosis are likely laminopathies and not due to 3β-hydroxysterol Δ14-reductase deficiency

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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 Δ14-reductase domain. It previously has been proposed that LBR is the primary sterol Δ14-reductase and that HEM dysplasia and ichthyosis are inborn errors of cholesterol synthesis. However, DHCR14 also encodes a sterol Δ14-reductase and could provide enzymatic redundancy with respect to cholesterol synthesis. To test the hypothesis that LBR and DHCR14 both function as sterol Δ14-reductases, we obtained ichthyosis mice (Lbr−/−) and disrupted Dhcr14. Heterozygous Lbr and Dhcr14 mice were intercrossed to test for a digenic phenotype. Lbr−/−, Dhcr14Δ4-7/Δ4-7 and Lbr+/−:Dhcr14Δ4-7/Δ4-7 mutant mice have distinct physical and biochemical phenotypes. Dhcr14Δ4-7/Δ4-7 mice are essentially normal, whereas Lbr+/−:Dhcr14Δ4-7/Δ4-7 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 Δ14-sterols were observed in Lbr−/− and Dhcr14Δ4-7/Δ4-7 brain tissue, and marked elevations were seen in Lbr+/−:Dhcr14Δ4-7/Δ4-7 brain. Pathological evaluation demonstrated vacuolation and swelling of the myelin sheaths in the spinal cord of Lbr+/−:Dhcr14Δ4-7/Δ4-7 mice consistent with a demyelinating process. This was not observed in either Lbr−/− or Dhcr14 Δ4-7/Δ4-7 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.

Journal Article.  6695 words.  Illustrated.

Subjects: Genetics and Genomics

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