Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q8NEX9 (reductase)
 26,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Smith-Lemli-Opitz syndrome (SLOS) in human infants is a common autosomal recessive malformation syndrome (estimated incidence, 1:20,000). It is characterized clinically by congenital anomalies, especially craniofacial and limb defects, and biochemically by a defect in 7-dehydrocholesterol-delta7-reductase activity (7DHC-reductase), the final enzyme in cholesterol biosynthesis. In previous studies, early administration of the 7DHC-reductase inhibitor AY9944 to pregnant rats resulted in a high frequency of holoprosencephaly, relevant to craniofacial anomalies of SLOS. In order to test the effect of AY9944 on limb development, we treated dams on gestation day 7 (GD7), which delays the biochemical defect to about GD13 to GD14. Sera were sampled on GD12, GD14, and GD21 and cholesterol and dehydrocholesterols (7DHC and 8DHC) were measured by gas-chromatography-mass spectrometry (GC-MS), as for the diagnosis of SLOS. GD21 fetuses were examined for gross malformations and skeletal development. In treated dams, the SLOS biochemical marker 7DHC accounted for one fourth and one third of total sterols, respectively, on GD12 and GD14, and cholesterolemia on these two gestation days was reduced by 50% and 43%, respectively, as compared with control values. This maternal metabolic defect was associated with decrease in fetal weight and delayed ossification. In addition, scapular malformations were observed in four fetuses from three litters. The malformations could have been caused by the same mechanism as holoprosencephaly after early treatment with AY9944. These cholesterol-deficiency-based malformations could have a common cause in the abnormal expression of Hedgehog or other developmental gene proteins, and may thus explain various congenital polymalformative syndromes in humans, including SLOS.
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PMID:Abnormal cholesterol biosynthesis as in Smith-Lemli-Opitz syndrome disrupts normal skeletal development in the rat. 952 40

The Smith-Lemli-Opitz syndrome (SLOS; also known as "RSH syndrome" [MIM 270400]) is an autosomal recessive multiple malformation syndrome due to a defect in cholesterol biosynthesis. Children with SLOS have elevated serum 7-dehydrocholesterol (7-DHC) levels and typically have low serum cholesterol levels. On the basis of this biochemical abnormality, it has been proposed that mutations in the human sterol Delta7-reductase (7-DHC reductase; E.C.1.3.1.21) gene cause SLOS. However, one could also propose a defect in a gene that encodes a protein necessary for either the expression or normal function of sterol Delta7-reductase. We cloned cDNA encoding a human sterol Delta7-reductase (DHCR7) on the basis of its homology with the sterol Delta7-reductase from Arabidopsis thaliana, and we confirmed the enzymatic function of the human gene product by expression in SLOS fibroblasts. SLOS fibroblasts transfected with human sterol Delta7-reductase cDNA showed a significant reduction in 7-DHC levels, compared with those in SLOS fibroblasts transfected with the vector alone. Using radiation-hybrid mapping, we show that the DHCR7 gene is encoded at chromosome 11q12-13. To establish that defects in this gene cause SLOS, we sequenced cDNA clones from SLOS patients. In three unrelated patients we have identified four different mutant alleles. Our results demonstrate both that the cDNA that we have identified encodes the human sterol Delta7-reductase and that mutations in DHCR7 are responsible for at least some cases of SLOS.
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PMID:Mutations in the human sterol delta7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome. 963 33

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 Delta7-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 fluorescense 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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PMID:Mutations in the Delta7-sterol reductase gene in patients with the Smith-Lemli-Opitz syndrome. 965 61

Smith-Lemli-Opitz syndrome is a frequently occurring autosomal recessive developmental disorder characterized by facial dysmorphisms, mental retardation, and multiple congenital anomalies. Biochemically, the disorder is caused by deficient activity of 7-dehydrocholesterol reductase, which catalyzes the final step in the cholesterol-biosynthesis pathway-that is, the reduction of the Delta7 double bond of 7-dehydrocholesterol to produce cholesterol. We identified a partial transcript coding for human 7-dehydrocholesterol reductase by searching the database of expressed sequence tags with the amino acid sequence for the Arabidopsis thaliana sterol Delta7-reductase and isolated the remaining 5' sequence by the "rapid amplification of cDNA ends" method, or 5'-RACE. The cDNA has an open reading frame of 1,425 bp coding for a polypeptide of 475 amino acids with a calculated molecular weight of 54.5 kD. Heterologous expression of the cDNA in the yeast Saccharomyces cerevisiae confirmed that it codes for 7-dehydrocholesterol reductase. Chromosomal mapping experiments localized the gene to chromosome 11q13. Sequence analysis of fibroblast 7-dehydrocholesterol reductase cDNA from three patients with Smith-Lemli-Opitz syndrome revealed distinct mutations, including a 134-bp insertion and three different point mutations, each of which was heterozygous in cDNA from the respective parents. Our data demonstrate that Smith-Lemli-Opitz syndrome is caused by mutations in the gene coding for 7-dehydrocholesterol reductase.
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PMID:Smith-Lemli-Opitz syndrome is caused by mutations in the 7-dehydrocholesterol reductase gene. 968 18

The RSH/Smith-Lemli-Opitz syndrome (RSH/SLOS) is an autosomal recessive malformation syndrome comprising microcephaly, developmental and growth retardation, characteristic facial anomalies, midline cleft palate, and genital and limb anomalies. Recently, biochemical evidence of an inborn error of cholesterol biosynthesis at the level of 7-dehydrocholesterol (7DHC) reductase was reported in children and adults with RSH/SLOS. We report on two sibs with a variant form of RSH/SLOS whose sterol metabolism in cultured lymphoblasts is abnormal but differs from that of patients with classical RSH/SLOS. The children have relatively mild physical and developmental abnormalities, but a phenotype still consistent with the diagnosis of RSH/SLOS. Their plasma cholesterol levels are only mildly depressed, and they have less markedly increased plasma levels of 7DHC than most patients with classical RSH/SLOS. Cultured lymphoblasts from our patients accumulated 7DHC to the same degree as classical RSH/SLOS lymphoblast when grown with cholesterol-depleted fetal calf serum. However, unlike other RSH/SLOS cells, the increase in cellular 7DHC levels was not suppressed when the cells were grown in the presence of cholesterol from untreated fetal calf serum. The parents' sterol metabolism was also strikingly abnormal in that the levels of 7DHC in their lymphoblasts were markedly elevated compared with those of lymphoblasts from other RSH/SLOS parents. Our findings suggest that these mildly affected RSH/SLOS sibs may have a genetic disorder of sterol metabolism that is related to but biochemically different from classical RSH/SLOS, possibly one affecting intracellular transport of sterols.
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PMID:Variant RSH/Smith-Lemli-Opitz syndrome with atypical sterol metabolism. 971 6

Smith-Lemli-Opitz syndrome (SLO) is caused by inherited enzymatic deficiency of 7-dehydrocholesterol-delta7-reductase and resultant cholesterol deficiency. It comprises a characteristic combination of facial features, malformations, and mental retardation. We report on three related patients (two brothers and their first cousin) with mental retardation and minimal physical signs in whom the diagnosis of SLO was delayed for a number of years. The presence of a third-degree relative in the absence of consanguinity in this family supports the proposed high population carrier frequency. Our report suggests that cases of mild SLO remain undiagnosed and untreated, and that awareness of this common cause of mental retardation is low.
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PMID:Smith-Lemli-Opitz syndrome: phenotypic extreme with minimal clinical findings. 971 7

The activity of ergosterol delta 7-reductase (3 beta-hydroxysteroid delta 7-reductase) was measured in cultured skin fibroblasts from 7 controls, 10 Smith-Lemli-Opitz syndrome (SLOS) patients, and 10 parents (obligate carriers). The fibroblasts were exposed to delipidated medium supplemented with lovastatin for 24 h and the enzyme activity was determined by incubating cell-free homogenate with ergosterol (ergosta-5,7,22-trien-3 beta-ol) and measuring the mass of brassicasterol (ergosta-5,22-dien-3 beta-ol) formed by gas chromatography-mass spectrometry with selected-ion monitoring. In carriers, the activity was significantly lower than in controls (22 +/- 2 vs 65 +/- 10 pmol/min per mg protein, p < 0.0005), and no overlap was observed. The mean activity in carriers' fibroblasts was more than 100 times higher than in patients' cells (0.2 pmol/min per mg protein). The use of ergosterol avoids the many problems caused by the instability and lack of availability of radiolabelled 7-dehydrocholesterol. The present method makes it possible to discriminate SLOS carriers from both controls and patients using a commercially available substrate and common analytical equipment.
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PMID:Accurate detection of Smith-Lemli-Opitz syndrome carriers by measurement of the rate of reduction of the ergosterol C-7 double bond in cultured skin fibroblasts. 981 6

7-Dehydrocholesterol accumulates in fetuses affected by the Smith-Lemli-Opitz syndrome as a result of a deficit in the ultimate step of cholesterol synthesis catalyzed by Delta7 reductase. Rat embryos explanted at gestation day 10 and cultured for 48 h in the presence of the Delta7 reductase inhibitor AY 9944 were used as a model to discriminate between the beneficial effect of supplementation with cholesterol and the deleterious effect of supplementation with 7-dehydrocholesterol. Cholesterol supplementation in the form of mixed cholesterol/lecithin liposomes added to serum serving as the culture medium restores the growth of embryos which is markedly decreased in the presence of the inhibitor. 7-Dehydrocholesterol under identical conditions does not restore growth and impairs the beneficial effect of cholesterol added simultaneously. UV-photooxidation of 7-dehydrocholesterol-supplemented culture medium enhances its embryotoxicity, which suggests uptake by the embryo of toxic by-products formed from 7-dehydrocholesterol. By contrast photooxidation of cholesterol-supplemented culture medium does not induce embryotoxicity. alpha-Tocopherol reduces the toxicity of photooxidized 7-dehydrocholesterol supplementing the culture medium. We conclude that 7-dehydrocholesterol does not fulfill the cholesterol requirement of the developing embryos and exerts an additional embryotoxic effect probably via oxidized by-products. This could explain the antenatal growth retardation of SLOS by a blockage of the maternal compensatory cholesterol influx.
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PMID:Oxidized derivatives of 7-dehydrocholesterol induce growth retardation in cultured rat embryos: a model for antenatal growth retardation in the Smith-Lemli-Opitz syndrome. 1006 34

The RSH/Smith-Lemli-Opitz syndrome (RSH/SLOS) is a relatively common, autosomal recessive malformation syndrome comprising distinctive facial, limb and genital anomalies, and mental retardation. Most patients with a clinical diagnosis of RSH/SLOS have a defect of cholesterol biosynthesis at the level of 3beta-hydroxysteroid-delta7-reductase, resulting in a decreased level of cholesterol and an increased level of 7-dehydrocholesterol (7DHC) in body fluids and tissues. We report on our experience with the prenatal diagnosis of RSH/SLOS by quantitative sterol chromatography in amniotic fluid (AF) and chorionic villus (CV). Of 76 AF and nine CV samples analyzed for various indications, 20 were diagnostic of RSH/SLOS based on an increased level of 7DHC in the fluid or tissue. Of 39 fetuses at a 25% risk for RSH/SLOS, 10(25.6%) were affected. Twenty-nine pregnancies not known to be at risk for RSH/SLOS were studied because of either a fetal abnormality characteristic of RSH/SLOS detected by ultrasound, a low maternal serum uE3 level (MSuE3), or both. None of the pregnancies tested, because of a low MSuE3 but lacking a sonographic abnormality characteristic of RSH/SLOS, was affected. However, three of four pregnancies with a low MSuE3 and an RSH/SLOS-type fetal abnormality were positive. RSH/ SLOS was diagnosed in two additional pregnancies on which MSuE3 data were not available but in which fetal anomalies were identified. Of these five RSH/SLOS fetuses identified in pregnancies not otherwise at risk for RSH/SLOS, the presenting sonographic anomaly was either polydactyly, ambiguous genitalia, or both. Evaluation of the biochemical parameters and clinical severity of RSH/SLOS showed that there was an inverse correlation between clinical severity and both the level of AF 7DHC and the level of MSuE3. Based on these earlier and more extensive studies, we conclude that accurate prenatal diagnosis of RSH/ SLOS is possible by sterol analysis of AF and, most likely, CV specimens as well. Furthermore, our findings suggest that MSuE3 levels in combination with sonography may provide useful diagnostic and prognostic information in the absence of a family history of RSH/SLOS.
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PMID:Prenatal diagnosis of the RSH/Smith-Lemli-Opitz syndrome. 1006 7

The equine-type estriols 1,3,5(10),7-estratetraene-3,16alpha,17beta-triol (16alpha-hydroxy-17beta-dihydroequilin) and 1,3,5(10),6,8-estrapentaene-3,16alpha,17beta-triol (16alpha-hydroxy-17beta-dihydroequilenin) constituted over half of the estrogens excreted by a woman carrying a Smith-Lemli-Opitz syndrome (SLOS) affected fetus. The steroids were characterized by gas chromatography-mass spectrometry (GC/MS), and mass spectra of the dehydro estriols as trimethylsilyl ethers are illustrated. SLOS is associated with 7-dehydrocholesterol (7DHC), delta 7-reductase deficiency; the enzyme catalyzing the final step in cholesterol biosynthesis. Identification of these equine estrogens show that an estrogen biosynthetic pathway parallel to normal is functional in the feto-placental unit and uses 7DHC as precursor, therefore P450scc, P450c17, and 3betaHSD and P450arom are all active on 7-dehydrometabolites. Patients with affected fetuses have low plasma estriol values (probably due to deficient production of the cholesterol precursor) and this is often a warning sign which instigates further evaluation for SLOS. The estriol deficiency is not quantitatively made up by the dehydrometabolites, and the combined excretion was found to be about one-third of the mean of gestational age matched controls. The importance of these findings lies in the potential value of dehydroestriol measurement for non-invasive diagnosis of SLOS at mid-gestation. Currently diagnosis relies on imaging, since SLOS is a malformation syndrome, and measurement of 7DHC levels in amniotic fluid and chorionic villus tissue.
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PMID:Equine type estrogens produced by a pregnant woman carrying a Smith-Lemli-Opitz syndrome fetus. 1008 12


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