Biochemical variants of Smith-Lemli-Opitz syndrome

Abstract

Smith-Lemli-Opitz (SLO or RSH) syndrome is characterized by multiple congenital anomalies, mental retardation, and defective growth; it results from an inherited defect in the biosynthesis of cholesterol. Patients have elevated plasma concentrations of 7-dehydrocholesterol, the immediate biosynthetic precursor of cholesterol and most also have low circulating levels of cholesterol. To understand better the biochemical basis of clinical variability, we evaluated cholesterol biosynthesis in lymphoblasts from 3 unrelated SLOS patients with distinct phenotypes. One patient has "type I SLOS", the second has the more severe "type II SLOS" and the third is classified as atypical and had been postulated to have a defect in sterol transport. The lymphoblasts of each patient show normal subcellular localization of cholesterol and 7-dehydrocholesterol by gradient fractionation. Biochemical differences in the ability of the lymphoblasts to convert 7-dehydrocholesterol to cholesterol are described and correspond to the severity of disease (type II > type I > atypical). Recently, the gene responsible for most SLOS cases (DHCR7) was mapped to chromosome 11 and mutations in DHCR7 were found in each of these patients. The biochemical differences described here likely result from the different mutations observed in DHCR7.

Frequency gradients of DHCR7 mutations in patients with Smith-Lemli-Opitz syndrome in Europe: evidence for different origins of common mutations

“…Twenty-six of these have been previously identified by us 15,18 and others. 16,17,19,[24][25][26] Six of the mutations have not been described before (T154R, M270V, G309S, R443H, I178N, R242H). No mutation was found on four out of 118 SLOS chromosomes from four patients (96.6% mutation-detection rate).…”

Cholesterol and Development: The RSH ("Smith-Lemli-Opitz") Syndrome and Related Conditions

“…However, Cunni¡ et al [1997] and Kelley and Herman [2001] have pointed out the existence of clinically typical RSH patients with normal plasma cholesterol levels and only mildly increased or even normal 7-DHC levels. When cells from these patients are cultured in lipiddeprived media, the level of intracellular 7-DHC often rises to the same level found in cells from typical RSH patients [Anderson et al,1998;Neklason et al,1999], suggesting that rapidly growing cells in tissue culture may re£ect better the sterol metabolism of rapidly dividing and di¡erentiating embryonic cells.…”

“…The arginine at 242 is absolutely conserved between human DHCR7, Arabidopsis thaliana sterol D7 reductase, the human laminin B receptor, Saccharomyces cerevisiae sterol D14-reductase, and S. cerevisiae D24(28)-reductase [Waterham et al, 1998]. The R450L mutation is in the carboxy terminus, which is an uncommon site for DHCR7 mutations [Neklason et al,1999].Whether these mutations a¡ect the activity of the enzyme is presently unknown; however, at the moment this unique form of RSH syndrome can only be regarded as an example of variability due to allelic rather than locus heterogeneity. More about gene structure and mutations follows.…”

Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models

“…Myelin defects due to reduced cholesterol levels are possibly found in Smith-Lemli-Opitz syndrome (SLOS), which is caused by mutations in the gene encoding sterol delta-7-reductase (DHCR7), the enzyme catalyzing the last step of cholesterol biosynthesis. This results in the elevation of the cholesterol precursors 7-dehydro-cholesterol and 8-dehydro-cholesterol and in cholesterol defi ciency in all tissues (33)(34)(35). Patients with SLOS have multiple malformations, cognitive impairment, and behavioral defi cits.…”

“…by guest, on www.jlr.org Downloaded from between the robust hypomyelination observed in SQS mouse mutants and the mild myelin defects observed in human SLOS is unclear, but may be related to the low amounts of cholesterol that are still produced in some forms of SLOS ( 33 ) and/or to the position of the defects leading to disruption of the cholesterol biosynthesis pathway, which is more upstream in SQS mouse mutants. Whereas the amount of myelin in SQS conditional mutants was decreased, its ultrastructure, lipid, and protein composition were not affected, suggesting a tight control mechanism matching the amount of myelin proteins produced by glial cells to the available cholesterol.…”