HEM Dysplasia and Mouse Ichthyosis are not due to Sterol 14-Reductase Deficiency. C.A. Wassif¹, K.E. Brownson¹, W.K. Wilson², M.F. Starost³, F.D. Porter¹. 1) Heritable Disorders Branch, NICHD, NIH, Bethesda, MD; 2) Rice University, Houston, TX; 3) DVR, OD, Bethesda, MD.
   Mutations of the lamin B receptor (LBR) have been shown to cause HEM dysplasia in humans and Ichthyosis in mice. LBR has both a lamin B binding and a sterol 14-reductase domain. Although only a minor sterol abnormality has been observed, it has been proposed that LBR is the primary sterol 14-reductase, and that impaired sterol 14-reduction underlies HEM dysplasia. However, DHCR14 also encodes a sterol 14-reductase. To test the hypothesis that LBR and DHCR14 are redundant sterol 14-reductases, we obtained Ichthyosis mice (Lbr-/-) and disrupted Dhcr14. Dhcr14-/- mice are phenotypically normal. No sterol abnormalities were found in either Lbr-/- or Dhcr14-/- tissues at 1 and 21 days of age. We then bred these mice to obtain compound mutant mice. Lbr-/-:Dhcr14-/- and Lbr-/-:Dhcr14+/- die in utero. Lbr+/-:Dhcr14-/- mice appear normal at birth, but by 10 days of age they are growth retarded and neurologically abnormal (ataxia and tremors). Pathological evaluation demonstrated vacuolation of and swelling of the myelin sheaths in the spinal cord consistent with a demyelinating process. This was not observed in either Lbr-/- or Dhcr14-/- mice. In contrast to Lbr-/- mice, Lbr+/-:Dhcr14-/- mice had normal skin and did not have Pelger-Huët anomaly. Peripheral tissue sterols were normal in all three mutant mice. However, significantly elevated levels (50% of total sterols) of cholesta-8,14-dien-3-ol and cholesta-8,14,24-trien-3-ol were found in brain tissue from 10 day-old Lbr+/-:Dhcr14-/- mice. Sterols were identified by GC/MS and NMR. These sterols were undetectable in Lbr-/- brain and only present at trace levels in Dhcr14-/- brain. Analysis of LBR and DHCR14 in human control and HEM dysplasia fibroblasts supports the redundant nature of these two proteins with respect to sterol 14-reduction. Our data supports the idea that HEM dysplasia and Ichthyosis are due to impaired lamin B receptor function rather than impaired sterol 14-reduction. Impaired sterol 14-reduction gives rise to a novel murine phenotype for which a corresponding human disorder has yet to be identified.