3β-Hydroxysterol Δ7-reductase and the Smith-Lemli-Opitz syndrome

Unit on Molecular Dysmorphology, Heritable Disorders Branch, Department of Health and Human Services, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Molecular Genetics and Metabolism (Impact Factor: 2.63). 03/2005; 84(2):112-26. DOI: 10.1016/j.ymgme.2004.09.017
Source: PubMed


In the final step of cholesterol synthesis, 7-dehydrocholesterol reductase (DHCR7) reduces the double bond at C7-8 of 7-dehydrocholesterol to yield cholesterol. Mutations of DHCR7 cause Smith-Lemli-Opitz syndrome (SLOS). Over 100 different mutations of DHCR7 have been identified in SLOS patients. SLOS is a classical multiple malformation, mental retardation syndrome, and was the first human malformation syndrome shown to result from an inborn error of cholesterol synthesis. This paper reviews the biochemical, molecular, and mutational aspects of DHCR7.

33 Reads
  • Source
    • "There is no strict genotype phenotype correlation, and most patients are compound heterozygotes [Correa-Cerro et al., 2005]. DHCR7 is located on chromosome 11q12-13 [Fitzky et al., 1998; Waterham et al., 1998; Wassif et al., 1998] and is expressed in all tissues. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Smith-Lemli-Opitz syndrome (SLOS) is a multiple malformation syndrome due to mutations of the 7-dehydrocholesterol reductase gene (DHCR7), which leads to a deficiency of cholesterol synthesis and an accumulation of 7-dehydrocholesterol. The SLOS clinical spectrum ranges from multiple major malformations to a mild phenotype with minor anomalies and intellectual disability. Several children with SLOS and adrenal insufficiency have been described. We performed ovine corticotropin (oCRH) testing in 35 SLOS patients and 16 age- and gender-matched controls. We reviewed prior adrenocorticotropin (ACTH) stimulation tests of our SLOS patients (19 of 35 available) and reviewed results of ACTH stimulation tests from 10 additional SLOS patients. Results from oCRH testing showed that patients with SLOS had significantly higher ACTH baseline values than healthy controls (24.8 ± 15.3 pg/ml vs. 17.8 ± 7.5 pg/ml, P = 0.034). However, no statistically significant differences were noted for peak ACTH values (74.4 ± 35.0 pg/ml vs. 64.0 ± 24.9 pg/ml, P = 0.303) and for baseline (14.2 ± 7.8 mcg/dl vs. 14.2 ± 6.3 mcg/dl, P = 0.992) and peak cortisol values (28.2 ± 7.9 mcg/dl vs. 24.8 ± 8.1 mcg/dl, P = 0.156). The area-under-the-curve (AUC) was not significantly different in SLOS patients compared to controls for both ACTH (250.1 ± 118.7 pg/ml vs. 195.3 ± 96.6 pg/ml, P = 0.121) as well as cortisol secretion (83.1 ± 26.1 mcg/dl vs. 77.8 ± 25.9 mcg/dl, P = 0.499). ACTH stimulation test results were normal in 28 of 29 tests. The individual with the abnormal test results had subsequent normal oCRH tests. The slightly increased baseline ACTH level seen during oCRH testing may be due to compensated adrenocortical insufficiency. However, we were able to show that our patients with SLOS had an adequate glucocorticoid response, and thus, in mild to moderate cases of SLOS stress steroid coverage may not be warranted.
    American Journal of Medical Genetics Part A 11/2011; 155A(11):2732-8. DOI:10.1002/ajmg.a.34271 · 2.16 Impact Factor
  • Source
    • "Hydrogen atoms are excluded for clarity. between CHOL and 7DHC in their interaction with membranes remains in large measure incomplete [6] [7]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Smith-Lemli-Opitz syndrome, a congenital and developmental malformation disease, is typified by abnormal accumulation of 7-dehydrocholesterol (7DHC), the immediate precursor of cholesterol (CHOL), and depletion thereof. Knowledge of the effect of 7DHC on the biological membrane is, however, still fragmentary. In this study, large-scale atomistic molecular dynamics simulations, employing two distinct force fields, have been conducted to elucidate differences in the structural properties of a hydrated dimyristoylphosphatidylcholine bilayer due to CHOL and 7DHC. The present series of results indicate that CHOL and 7DHC possess virtually the same ability to condense and order membranes. Furthermore, the condensing and ordering effects are shown to be strengthened at increasing sterol concentrations.
    Physical Biology 08/2011; 8(5):056005. DOI:10.1088/1478-3975/8/5/056005 · 2.54 Impact Factor
  • Source
    • "The c.964-1G>C (IVS8-1 G>C) allele is the most common mutation, (Battaile et al. 2001; Correa-Cerro and Porter 2005; Waye et al. 2002; Wright et al. 2003) accounting for about a third of ascertained alleles. IVS8-1 G>C is a splice acceptor mutation and is a null mutation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Smith-Lemli-Opitz syndrome (SLOS) is a malformation syndrome resulting from mutations of the 7-dehydrocholesterol reductase (DHCR7) gene. During cholesterol biosynthesis, DHCR7 catalyzes the conversion of 7-dehydrocholesterol (7DHC) to cholesterol. A clinical diagnosis of SLOS is confirmed biochemically by the presence of elevated levels of 7DHC. Phenotypic severity of SLOS has previously been shown to correlate with the 7DHC/cholesterol ratio. We describe a patient with a severe SLOS phenotype, but a very low serum 7DHC/cholesterol ratio. We show that this discordance is due to alternative splicing of a previously unreported IVS5+3 A>T mutation. This mutation results in the transcription of both normal and mutant mRNA transcripts. We postulate that alternative splicing of the IVS5+3 A>T results in insufficient DHCR7 activity during embryogenesis, but sufficient DHCR7 activity once cholesterol synthetic rates decrease postnatally. This unique case underscores the adjunctive use of fibroblast and molecular testing in ambiguous cases of SLOS and may provide insight into the potential efficacy of therapeutic interventions altering postnatal cholesterol biosynthesis.
    American Journal of Medical Genetics Part A 08/2010; 152A(8):2094-8. DOI:10.1002/ajmg.a.33540 · 2.16 Impact Factor
Show more


33 Reads
Available from