Markedly inhibited 7-dehydrocholesterol-delta 7-reductase activity in liver microsomes from Smith-Lemli-Opitz homozygotes.

Shefer, Sarah; Salen, Gerald; Batta, Ashok K.; Honda, Akira; Tint, G. S.; Irons, Mira; Elias, Ellen Roy; Chen, Thomas; Holick, Michael F.

doi:10.1172/jci118223

Cited by 125 publications

(80 citation statements)

References 23 publications

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“…Liver microsomes from patients with fatal SLOS showed a residual 7-dehydrocholesterol metabolism of 10% (17). A likely explanation is that one of the two DHCR7 alleles is not completely inactivated in line with the results of the molecular analysis: in seven patients, a putative null allele is combined with a missense mutation.…”

Section: Discussionmentioning

confidence: 80%

Mutations in the Δ7-sterol reductase gene in patients with the Smith–Lemli–Opitz syndrome

Fitzky

Witsch‐Baumgartner

Erdel

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

371

362

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The Smith-Lemli-Opitz syndrome (SLOS) is an inborn disorder of sterol metabolism with characteristic congenital malformations and dysmorphias. All patients suffer from mental retardation. Here we identify the SLOS gene as a ⌬7-sterol reductase (DHCR7, EC 1.3.1.21) required for the de novo biosynthesis of cholesterol. The human and murine genes were characterized and assigned to syntenic regions on chromosomes 11q13 and 7F5 by f luorescense in situ hybridization. Among the mutations found in patients with the SLOS, are missense (P51S, T93M, L99P, L157P, A247V, V326L, R352W, C380S, R404C, and G410S), nonsense (W151X), and splice site (IVS8-1G>C) mutations as well as an out of frame deletion (720-735 del). The missense mutations L99P, V326L, R352W, R404C, and G410S reduced heterologous protein expression by >90%. Our results strongly suggest that defects in the DHCR7 gene cause the SLOS.

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Section: Discussionmentioning

confidence: 80%

Mutations in the Δ7-sterol reductase gene in patients with the Smith–Lemli–Opitz syndrome

Fitzky

Witsch‐Baumgartner

Erdel

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

371

362

View full text Add to dashboard Cite

show abstract

“…The most common of the defects is the Smith-Lemli-Opitz syndrome (SLOS). Individuals with this syndrome have mutations in 3β-hydroxysterol Δ 7 -reductase (DHCR7) and convert minimal to no 7-dehydrocholesterol to cholesterol, depending on the type of mutation [4,5]. The deficiency of cholesterol can lead to a wide range of congenital defects, ranging from the mild (minor physical abnormality with behavioral and learning disabilities) to the severe (lethal with multiple major congenital anomalies) [6,7].…”

Section: Introductionmentioning

confidence: 99%

Inability to fully suppress sterol synthesis rates with exogenous sterol in embryonic and extraembyronic fetal tissues

Yao

Jenkins

Horn

et al. 2007

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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SUMMARYThe requirement for cholesterol is greater in developing tissues (fetus, placenta, and yolk sac) as compared to adult tissues. Here, we compared cholesterol-induced suppression of sterol synthesis rates in the adult liver to the fetal liver, fetal body, placenta, and yolk sac of the Golden Syrian hamster. Sterol synthesis rates were suppressed maximally in non-pregnant adult livers when cholesterol concentrations were increased. In contrast, sterol synthesis rates were suppressed only marginally in fetal livers, fetal bodies, placentas, and yolk sacs when cholesterol concentrations were increased. To begin to elucidate the mechanism responsible for the blunted response of sterol synthesis rates in fetal tissues to exogenous cholesterol, the ratio of sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) to Insig-1 was measured in these same tissues since the ratio of SCAP to the Insigs can impact SREBP processing. The fetal tissues had anywhere from a 2-to 6-fold greater ratio of SCAP to Insig-1 than did the adult liver, suggesting constitutive processing of the SREBPs. As expected, the level of mature, nuclear SREBP-2 was not different in the fetal tissues with different levels of cholesterol whereas it was different in adult livers. These findings indicate that the suppression of sterol synthesis to exogenous sterol is blunted in developing tissues and the lack of response appears to be mediated at least partly through relative levels of Insigs and SCAP.

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“…reductase (DHCR7) [4,5], which converts 7-dehydrocholesterol (7-DHC) to cholesterol, due to mutations in DHCR7 [6][7][8]. As might be expected, SLOS is characterized by a reduction in cholesterol and an increase in cholesterol precursors, including 7-and 8-DHC.…”

mentioning

confidence: 88%

“…Individuals with a severe phenotype have many congenital abnormalities and mental retardation whereas those with a mild phenotype may have only subtle learning disorders and minor dysmorphic features [1][2][3]. The biochemical cause of this syndrome is a reduction in the activity of the enzyme 7-dehydrocholesterol-Δ7- [4,5], which converts 7-dehydrocholesterol (7-DHC) to cholesterol, due to mutations in DHCR7 [6][7][8]. As might be expected, SLOS is characterized by a reduction in cholesterol and an increase in cholesterol precursors, including 7-and 8-DHC.…”

mentioning

confidence: 99%

Enhanced placental cholesterol efflux by fetal HDL in Smith–Lemli–Opitz syndrome

Jenkins

Merkens

Tubb

et al. 2008

Molecular Genetics and Metabolism

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Previous studies from this laboratory have shown that maternal-derived cholesterol can be effluxed from trophoblasts to fetal HDL and plasma. We had the opportunity to study for the first time the ability of HDL and plasma from a fetus with the Smith-Lemli-Opitz syndrome (SLOS) to efflux cholesterol from trophoblasts. It was unclear whether cholesterol could be effluxed to fetuses with SLOS since lipoprotein levels are often very low. To answer this question, cord blood was collected from the placentas of an SLOS fetus and unaffected fetuses just after delivery. Plasma cholesterol concentrations were very low in the affected fetus; cholesterol, 7-dehydrocholesterol, and 8-dehydocholesterol concentrations were 14.1, 4.5, and 5.2 mg/dl, respectively. The HDL from the fetal SLOS effluxed ≈50% more cholesterol from a trophoblast cell line, were smaller in size, and had a lower cholesterol to phospholipid ratio as compared to HDL from unaffected fetuses or adults. Plasma from the SLOS fetus effluxed cholesterol to a similar percentage as unaffected fetal plasma or adult plasma, possibly due to fewer HDL particles as demonstrated in previous SLOS patients. These novel data demonstrate that the cholesteroldeficient SLOS fetus is able to obtain cholesterol from trophoblasts at a time when cholesterol is playing a critical role in development, and has implications for design of treatments for cholesterol deficiency syndromes as well as understanding of prenatal cholesterol transport in humans. KeywordsFetus; Trophoblast; BeWo cells; Pregnancy; Cholesterol transport Smith-Lemli-Opitz syndrome (SLOS) is a metabolic disorder that presents with a spectrum of congenital abnormalities. Individuals with a severe phenotype have many congenital abnormalities and mental retardation whereas those with a mild phenotype may have only subtle learning disorders and minor dysmorphic features [1][2][3]. The biochemical cause of this syndrome is a reduction in the activity of the enzyme 7-dehydrocholesterol-Δ7- [4,5], which converts 7-dehydrocholesterol (7-DHC) to cholesterol, due to mutations in DHCR7 [6][7][8]. As might be expected, SLOS is characterized by a reduction in cholesterol and an increase in cholesterol precursors, including 7-and 8-DHC. Recent studies demonstrate that the incidence of this syndrome may be much greater than previously believed at a predicted incidence of 1:1590-1:13,500 [9,10], though observed incidence is lower (perhaps 1 in 20,000 births). The discrepancy in observed versus predicted incidence is likely due in part to pregnancy loss as well as undiagnosed mild cases. Nevertheless, SLOS is probably the second most prevalent, potentially lethal, recessive genetic condition behind cystic fibrosis with an incidence of 1:2500 [11]. The congenital malformations associated with this disease can begin to appear as early as 3 weeks postconception when Sonic Hedgehog (SHH) is needed for patterning of the forebrain [12,13], since sterols activate SHH [14][15][16] and sterol deficiency is thought to play a rol...

show abstract

Markedly inhibited 7-dehydrocholesterol-delta 7-reductase activity in liver microsomes from Smith-Lemli-Opitz homozygotes.

Cited by 125 publications

References 23 publications

Mutations in the Δ7-sterol reductase gene in patients with the Smith–Lemli–Opitz syndrome

Mutations in the Δ7-sterol reductase gene in patients with the Smith–Lemli–Opitz syndrome

Inability to fully suppress sterol synthesis rates with exogenous sterol in embryonic and extraembyronic fetal tissues

Enhanced placental cholesterol efflux by fetal HDL in Smith–Lemli–Opitz syndrome

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