Smith-Lemli-Opitz (RHS) syndrome: holoprosencephaly and homozygous IVS8-1G?C genotype

Nowaczyk, Małgorzata J.M.; Farrell, Sandra A.; Sirkin, Wilma; Velsher, Leah; Krakowiak, Patrycja A.; Waye, John S.; Porter, Forbes D.

doi:10.1002/1096-8628(20010915)103:1<75::aid-ajmg1502>3.0.co;2-r

Cited by 45 publications

(29 citation statements)

References 22 publications

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“…This is a well-known mutation leading to a null allele of the delta-7-sterol reductase gene, which accounts for up to onethird of mutant alleles of SLOS patients in populations of European descent. Homozygotes of this splicing mutation are rarely seen in SLOS patients despite the high carrier frequency, and all manifest at the severe end of the SLOS phenotypic spectrum and are not known to survive through childhood 26,27 . Four other well-characterized recessive diseases were represented in our final list of candidates.…”

Section: Discussionmentioning

confidence: 99%

Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases

Chen¹,

Shi²,

Hakenberg³

et al. 2016

Nat Biotechnol

284

252

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Section: Discussionmentioning

confidence: 99%

Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases

Chen¹,

Shi²,

Hakenberg³

et al. 2016

Nat Biotechnol

284

252

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“…This results in low concentrations of cholesterol and high concentrations of 7-DHC in plasma and tissues (24)(25)(26). The clinical manifestations are diverse and include congenital malformations, facial anomalies, mental retardation, and behavioral problems (27,28).…”

Section: Discussionmentioning

confidence: 99%

Increased nonsterol isoprenoids, dolichol and ubiquinone, in the Smith-Lemli-Opitz syndrome: effects of dietary cholesterol

Pappu

Connor

Merkens

et al. 2006

Journal of Lipid Research

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Smith-Lemli-Opitz syndrome (SLOS) is an inherited autosomal recessive cholesterol deficiency disorder. Our studies have shown that in SLOS children, urinary mevalonate excretion is normal and reflects hepatic HMG-CoA reductase activity but not ultimate sterol synthesis. Hence, we hypothesized that in SLOS there may be increased diversion of mevalonate to nonsterol isoprenoid synthesis. To test our hypothesis, we measured urinary dolichol and ubiquinone, two nonsterol isoprenoids, in 16 children with SLOS and 15 controls, all fed a low-cholesterol diet. The urinary excretion of both dolichol (P , 0.002) and ubiquinone (P , 0.02) in SLOS children was 7-fold higher than in control children, whereas mevalonate excretion was comparable. In a subset of 12 SLOS children, a high-cholesterol diet decreased urinary mevalonate excretion by 61% (P , 0.001), dolichol by 70% (P , 0.001), and ubiquinone by 67% (P , 0.03). Our hypothesis that in SLOS children, normal urinary mevalonate excretion results from increased diversion of mevalonate into the production of nonsterol isoprenoids is supported. Dietary cholesterol supplementation reduced urinary mevalonate and nonsterol isoprenoid excretion but did not change the relative ratios of their excretion. Therefore, in SLOS, a secondary peripheral regulation of isoprenoid synthesis may be stimulated.-

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“…SLOS fetuses and newborns, even infants with the null/null genotype, contain cholesterol (21,22). Importantly, the severity of the SLOS phenotype is affected by the apoE isoform expressed in the mothers but not the fathers (23).…”

mentioning

confidence: 99%

Transport of maternal cholesterol to the fetus is affected by maternal plasma cholesterol concentrations in the Golden Syrian hamster

Burke

Colvin

Myatt

et al. 2009

Journal of Lipid Research

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The fetus has a high requirement for cholesterol and synthesizes cholesterol at elevated rates. Recent studies suggest that fetal cholesterol also can be obtained from exogenous sources. The purpose of the current study was to examine the transport of maternal cholesterol to the fetus and determine the mechanism responsible for any cholesterol-driven changes in transport. Studies were completed in pregnant hamsters with normal and elevated plasma cholesterol concentrations. Cholesterol feeding resulted in a 3.1-fold increase in the amount of LDL-cholesterol taken up by the fetus and a 2.4-fold increase in the amount of HDL-cholesterol taken up. LDL-cholesterol was transported to the fetus primarily by the placenta, and HDL-cholesterol was transported by the yolk sac and placenta. Several proteins associated with sterol transport and efflux, including those induced by activated liver X receptor, were expressed in hamster and human placentas: NPC1, NPC1L1, ABCA2, SCP-x, and ABCG1, but not ABCG8. NPC1L1 was the only protein increased in hypercholesterolemic placentas. Thus, increasing maternal lipoprotein-cholesterol concentrations can enhance transport of maternal cholesterol to the fetus, leading to 1) increased movement of cholesterol down a concentration gradient in the placenta, 2) increased lipoprotein secretion from the yolk sac (shown previously), and possi- Cholesterol is essential for normal fetal development. Possibly the most noted role of cholesterol is as a structural component of membranes. Sterols are also the precursor for bile acids, steroid hormones, and oxysterols, which are all synthesized by the fetus and regulate various cellular processes. Cholesterol is also required for activation of sonic hedgehog (Shh), a protein involved in brain development, and for propagation of the Shh signal (1, 2). Cholesterol is obtained endogenously by de novo synthesis and exogenously by transfer of maternal cholesterol to the fetus. Interestingly, maternal plasma triglyceride and cholesterol concentrations increase during pregnancy in humans (3, 4), possibly an adaptation to maternal and fetal needs. However, whether these changes in maternal lipoprotein concentrations result in increased transport of maternal cholesterol to the fetus is unclear.Since the fetus does not come in direct contact with the maternal circulation, maternal cholesterol destined for the fetus must initially be taken up by the placenta and yolk sac prior to transport and delivery to the fetus. Indeed, the placenta and yolk sac take up maternal LDL-and HDLcholesterol at relatively elevated rates compared with other peripheral tissues (5). LDL is taken up by the LDL receptor (LDLR), which is expressed abundantly in the placenta but expressed at low levels, if at all, in the yolk sac (5, 6). LDL-derived sterol is transported to the lysosome/endosome pathway where the ester bond is hydrolyzed (7). The unesterified cholesterol is then transported by NiemannThese studies were supported by grants HD34089 (LAW) and GM31651 (FS) from the...

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Smith-Lemli-Opitz (RHS) syndrome: holoprosencephaly and homozygous IVS8-1G?C genotype

Cited by 45 publications

References 22 publications

Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases

Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases

Increased nonsterol isoprenoids, dolichol and ubiquinone, in the Smith-Lemli-Opitz syndrome: effects of dietary cholesterol

Transport of maternal cholesterol to the fetus is affected by maternal plasma cholesterol concentrations in the Golden Syrian hamster

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