A mouse model for the Smith-Lemli-Opitz syndrome (SLOS). G.S. Tint1,2, H. Waage3, K.K. Sulik3, F.F. Moebius4, B.U. Fitzky4, H. Glossmann4, S. Shefer2, G. Salen1,2. 1) VA New Jersey Health Care System, East Orange, NJ; 2) UMDNJ-New Jersey Medical School, Newark, NJ; 3) University of North Carolina, Chapel Hill, NC; 4) Institute for Biochemical Pharmacology, Innsbruck, Austria.
SLOS is a not-uncommon severe birth defect-mental retardation syndrome caused by a defect in 7-dehydrocholesterol (7DHC) D7-reductase (DHCR7. E.C.1.3.1.21), the final enzyme in the cholesterol (CH) biosynthetic pathway. Children exhibit multiple abnormalities of face, limbs, genitalia and internal organs, develop slowly, are photosensitive, frequently exhibit destructive behaviors and have greatly reduced survival. Human DHCR7 contains 9 exons, spans 14 kb, is localized to 11q13 and codes for a 55 kDa protein. Using stem cell gene targeting we mutated this gene in the mouse to create an animal model for the syndrome. Matings of animals heterozygous for the targeted disruption have thus far resulted in 11 -/-, 20 +/-, and 7 +/+, which approximates the 1:2:1, expected ratio. The male to female ratio is also approximately as expected. The litters were of normal size, indicating that all pups survive to term. However, the homozygotes died shortly after birth (within about 14 hrs). Among the eleven -/- mice, two wide cleft palates were observed while abnormally distended bladders were also noted in 6 -/- mice predominately in males. DHCR7 activity in 8 -/- newborn mice was found to be ~ 1% of that in a control animal (26±20 vs. 2030pmol/min/mg protein). Liver 7DHC concentrations, undetectable in controls, were 0.43±0.24 mg/g in 8 -/- animals while CH levels averaged 0.69±0.50 mg/g (compared to 1.90±0.66 mg/g in 7 adult controls). In brain (n=3 -/-) the defect was far worse with mean CH and 7DHC levels of 0.41±0.03 and 1.19±0.23 mg/g, respectively, vs. 3.99 and <0.01 mg/g, respectively, in 2 +/- newborns. All of the biochemical parameters closely mirror the differences we see between the group of affected SLOS children who are in the middle range of clinical severity and age matched controls. Thus, the model appears to successfully model CH and 7DHC metabolism in about 50% of affected children.