HEM dysplasia and ichthyosis are likely laminopathies and not due to 3beta-hydroxysterol Delta14-reductase deficiency.

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 D14-reductase domain. It previously has been proposed that LBR is the primary sterol D14-reductase and that HEM dysplasia and ichthyosis are inborn errors of cholesterol synthesis. However, DHCR14 also encodes a sterol D14-reductase and could provide enzymatic redundancy with respect to cholesterol synthesis. To test the hypothesis that LBR and DHCR14 both function as sterol D14-reductases, we obtained ichthyosis mice (Lbr2/2) and disrupted Dhcr14. Heterozygous Lbr and Dhcr14 mice were intercrossed to test for a digenic phenotype. Lbr2/2, Dhcr14D4-7/D4-7 and Lbr1/2:Dhcr14D4-7/D4-7 mutant mice have distinct physical and biochemical phenotypes. Dhcr14D4-7/D4-7 mice are essentially normal, whereas Lbr1/2:Dhcr14D4-7/D4-7 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 D14-sterols were observed in Lbr2/2 and Dhcr14D4-7/D4-7 brain tissue, and marked elevations were seen in Lbr1/2:Dhcr14D4-7/D4-7 brain. Pathological evaluation demonstrated vacuolation and swelling of the myelin sheaths in the spinal cord of Lbr1/2:Dhcr14D4-7/D4-7 mice consistent with a demyelinating process.This was not observed in either Lbr2/2 or Dhcr14 D4-7/D4-7 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.