On the Role of Membrane Structural Defects in Smith-Lemli-Opitz Syndrome

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disease initially caused by mutations in the DHCR7 gene (OMIM# 602858); this gene encodes the penultimate enzyme in the cholesterol biosynthetic pathway, 7-dehydrocholesterol reductase (3β-hydroxysterol-Δ7-reductase; EC 1.3.1.21) [1,2]. Such mutations give rise to a catalytically defective enzyme, resulting in an inefficient conversion of 7-dehydrocholesterol (7DHC), the immediate biogenic precursor of cholesterol, to cholesterol. This causes aberrant accumulation of 7DHC (and, typically to a far lesser extent, its isomer, 8-dehydrocholesterol (8DHC)) and reduced levels of cholesterol in bodily tissues and fluids [3]. [Notably, there are no reports of an “all-or-none” effect, where cells or tissues from affected individuals or unborn fetuses contain no detectable residual cholesterol. More typically, the cholesterol levels are far below normal, while the dehydrosterol precursors are the dominant sterol species present.] The biological consequences of this biochemical defect, unlike many other monogenic diseases, can vary dramatically, with the severity of phenotypic abnormalities ranging from relatively mild to severe, even including embryonic or early neonatal lethality [1]. SLOS is considered a pediatric disorder, since the disease manifests in early childhood and few affected individuals survive beyond the teenage years.