Abnormal cholesterol biosynthesis in sitosterolaemia and the Smith-Lemli-Opitz syndrome

1996 ◽  
Vol 19 (4) ◽  
pp. 391-400 ◽  
Author(s):  
G. Salen ◽  
S. Shefer ◽  
A. K. Batta ◽  
G. S. Tint ◽  
G. Xu ◽  
...  
Keyword(s):  
Cholesterol Biosynthesis ◽  
Opitz Syndrome

scholarly journals 7-Dehydrocholesterol down-regulates cholesterol biosynthesis in cultured Smith-Lemli-Opitz syndrome skin fibroblasts

1998 ◽  
Vol 39 (3) ◽  
pp. 647-657 ◽  
Author(s):  
Megumi Honda ◽  
G.S. Tint ◽  
Akira Honda ◽  
Lien B. Nguyen ◽  
Thomas S. Chen ◽  
...  
Keyword(s):  
Cholesterol Biosynthesis ◽  
Skin Fibroblasts ◽  
Opitz Syndrome

scholarly journals Non-cell autonomous inhibition of the Shh pathway due to impaired cholesterol biosynthesis requires Ptch1/2

2020 ◽  
Author(s):  
Carian Jägers ◽  
Henk Roelink
Keyword(s):  
Sonic Hedgehog ◽  
Birth Defects ◽  
Cholesterol Synthesis ◽  
Cholesterol Biosynthesis ◽  
Shh Signaling ◽  
Shh Pathway ◽  
Opitz Syndrome ◽  
Cholesterol Precursors ◽  
G Protein Coupled ◽  
Mutant Cells

AbstractBirth defects due to congenital errors in enzymes involved cholesterol synthesis like Smith-Lemli-Opitz syndrome (SLOS) and Lathosterolosis cause an accumulation of cholesterol precursors and a deficit in cholesterol. The phenotype of both SLOS and Lathosterolosis have similarities to syndromes associated with abnormal Sonic hedgehog (Shh) signaling, consistent with the notion that impaired cholesterol signaling can cause reduced Shh signaling. Two multipass membrane proteins play central roles in Shh signal transduction, the putative Resistance, Nodulation and Division (RND) antiporters Ptch1 and Ptch2, and the G-protein coupled receptor Smoothened (Smo). Sterols have been suggested as cargo for Ptch1, while Smo activity can affected both positively and negatively by steroidal molecules. We demonstrate that mESCs mutant for 7-dehydroxycholesterol reductase (7dhcr) or sterol-C5-desaturase (sc5d) reduce the Hh response in nearby wildtype cells when grown in mosaic organoids. This non-cell autonomous inhibitory activity of the mutant cells required the presence of both Ptch1 and Ptch2. These observations support a model in which late cholesterol precursors that accumulate in cells lacking 7DHCR are the cargo for Ptch1 and Ptch2 activity that mediates the non-cell autonomous inhibition of Smo.

scholarly journals Smith–Lemli–Opitz Mutations in Unexplained Stillbirths

2018 ◽  
Vol 35 (10) ◽  
pp. 936-939 ◽  
Author(s):  
Uma Reddy ◽  
George Saade ◽  
Robert Goldenberg ◽  
Donald Dudley ◽  
Corette Parker ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Cholesterol Biosynthesis ◽  
Strong Association ◽  
Placental Tissue ◽  
Population Based ◽  
Poor Quality ◽  
Single Mutation ◽  
Live Births ◽  
Opitz Syndrome ◽  
Control Study

Objective Smith–Lemli–Opitz syndrome (SLOS) is an autosomal recessive syndrome caused by a defect in cholesterol biosynthesis with mutations in 7-dehydrocholesterol reductase (DHCR7). A total of 3% of Caucasians carry DHCR7 mutations, theoretically resulting in a homozygote frequency of 1/4000. However, SLOS occurs in only 1/20,000 to 60,000 live births. Our objective was to assess DHCR7 mutations in unexplained stillbirths. Study Design Prospective, multicenter, population-based case–control study of all stillbirths and a representative sample of live births enrolled in five geographic areas. Cases with stillbirth due to obstetric complications, infection, or aneuploidy, and those with poor quality deoxyribonucleic acid (DNA) were excluded. DNA was extracted from placental tissue stored at –80°C, and exons 3 to 9 of the DCHR7 gene were amplified, purified, and subjected to bidirectional sequencing to identify mutations. Results One-hundred forty four stillbirths were unexplained and had adequate DNA for analysis. Nine stillbirths of 139 (6.5%) had a single mutation in one allele in coding exons 3 to 9 of DHCR7 (Table 1). One case (0.7%) was a compound heterozygote for mutations in exons 3 to 9 of DHCR7; this fetus had no clinical or histologic features of SLOS. Conclusion We detected SLOS mutations in only 0.7% of stillbirths. This does not support a strong association between unrecognized DHCR7 mutations and stillbirth.

scholarly journals Dietary cholesterol supplementation and inhibitory factor 1 serum levels in two dizygotic Smith-Lemli-Opitz syndrome twins: a case report

2020 ◽  
Vol 46 (1) ◽  
Author(s):  
Maurizio Delvecchio ◽  
Biagio Rapone ◽  
Simonetta Simonetti ◽  
Simona Fecarotta ◽  
Graziana De Carlo ◽  
...  
Keyword(s):  
Cholesterol Biosynthesis ◽  
Neurodevelopmental Disorder ◽  
Mitochondrial Protein ◽  
Dietary Cholesterol ◽  
Hdl Cholesterol ◽  
Inhibitory Factor ◽  
Cholesterol Intake ◽  
Opitz Syndrome ◽  
Cholesterol Supplementation ◽  
Inhibitory Factor 1

Abstract Background Smith-Lemli-Opitz syndrome (SLOS) is a rare genetic neurodevelopmental disorder caused by the defect in the 7-dehydrocholesterol reductase. This defect leads to the deficiency of cholesterol biosynthesis with accumulation of 7-dehydrocholesterol. Inhibitory factor 1 (IF1) is a well-known mitochondrial protein. Recently, it has been discovered in the human serum where it is reported to be involved in the HDL-cholesterol intake. Here we report the IF1 presence in the serum of two paediatric SLOS dizygotic twins treated with dietary cholesterol supplementation. Case presentation The patients showed a typical phenotype. They started dietary supplementation with cholesterol when 2 months old. The cholesterol intake was periodically titrated on the basis of weight increase and the twin 1 required a larger supplementation than the twin 2 during the follow-up. When 6.4-year-old, they underwent IF1 assay that was 7-fold increased in twin 2 compared to twin 1 (93.0 pg/ml vs 13.0 pg/ml, respectively). Conclusions We report, for the first time, the presence of circulating IF1 in the serum of SLOS patients, showing different levels among them. Our findings confirm that IF1 could be a novel research target in cholesterol-related disorders and also in SLOS, and could contribute to the general debate on IF1 as a new modulator of cholesterol levels.

Precholesterol Sterols Accumulate in Lipid Rafts of Patients with Smith-Lemli-Opitz Syndrome and X-Linked Dominant Chondrodysplasia Punctata

2008 ◽  
Vol 11 (2) ◽  
pp. 128-132 ◽  
Author(s):  
Dinesh Rakheja ◽  
Richard L. Boriack
Keyword(s):  
Lipid Rafts ◽  
Hedgehog Signaling ◽  
Cholesterol Biosynthesis ◽  
Membrane Lipid ◽  
Chondrodysplasia Punctata ◽  
Autopsy Material ◽  
Cholesterol Levels ◽  
Abnormal Accumulation ◽  
Hedgehog Proteins ◽  
Opitz Syndrome

Systemic fetal dysmorphogenesis in disorders of postsqualene cholesterol biosynthesis is thought to be caused by disruption of Hedgehog signaling. Because precholesterol sterols such as 7-dehydrocholesterol and lathosterol can replace cholesterol in the activation of Hedgehog proteins, it is currently believed that cholesterol deficiency-related Hedgehog signaling block occurs further downstream, probably at the level of Smoothened. Experimentally, such a block in Hedgehog signaling occurs at sterol levels of <40 μg/mg protein. Recently, we studied autopsy material from 2 infants with fatal cholesterol biosynthetic disorders (Smith-Lemli-Opitz syndrome and X-linked dominant chondrodysplasia punctata) in which the hepatic cholesterol levels were far greater. In this study, we demonstrate abnormal accumulation of sterol precursors of cholesterol in membrane lipid rafts (detergent resistance membranes) prepared from liver tissues of these 2 infants: 8-dehydrocholesterol and 7-dehydrocholesterol in lipid rafts of the infant with Smith-Lemli-Opitz syndrome and cholest-8(9)-ene-3β-ol in lipid rafts of the infant with X-linked dominant chondrodysplasia punctata. We suggest that such alterations in the lipid raft sterol environment may affect the biology of cells and the development of fetuses with cholesterol biosynthetic disorders.

Hydrolethalus syndrome, in contrast to Smith-Lemli-Opitz syndrome, is not due to a defect in post-squalene cholesterol biosynthesis: A case report

2004 ◽  
Vol 129A (2) ◽  
pp. 212-213 ◽  
Author(s):  
Dinesh Rakheja ◽  
Michael L. Cimo ◽  
Ronald M. Ramus ◽  
Beverly B. Rogers ◽  
Michael J. Bennett ◽  
...  
Keyword(s):  
Case Report ◽  
Cholesterol Biosynthesis ◽  
Opitz Syndrome

A Case of Smith-Lemli-Opitz Syndrome, Defect of Cholesterol Biosynthesis

2006 ◽  
Vol 19 (2) ◽  
pp. 439-442 ◽  
Author(s):  
S. Domizio ◽  
R. Pallotta ◽  
A. Romanelli ◽  
C. Puglielli ◽  
R. Pollice ◽  
...  
Keyword(s):  
Cholesterol Biosynthesis ◽  
Opitz Syndrome

Smith-Lemli-Opitz Syndrome and Role of Cholesterol in Autism

2013 ◽  
Author(s):  
Geeta Sarphare ◽  
Ryan Lee ◽  
Elaine Tierney
Keyword(s):  
Cholesterol Biosynthesis ◽  
Critical Role ◽  
Autosomal Recessive Disorder ◽  
The United States ◽  
Mendelian Inheritance ◽  
The Body ◽  
European Ancestry ◽  
Embryonic And Fetal Development ◽  
Opitz Syndrome ◽  
Fat Soluble Vitamins

Cholesterol is manufactured throughout the body, but predominantly in the liver, and is essential for many metabolic processes. Cholesterol plays a critical role in forming membranes and myelin sheaths and is a precursor molecule for the synthesis of steroid hormones, neuroactive steroids, oxysterols, and vitamin D. It is also essential in the production of bile acids, which in turn helps the body absorb cholesterol and fat-soluble vitamins. Cholesterol is essential in embryonic and fetal development and is also critical in regulating lipid raft processes such as signaling and trafficking (Korade & Kenworthy, 2008). Cholesterol biosynthesis begins with the formation of squalene and ends with the reduction of 7-dehydrocholesterol (7DHC) into cholesterol by the enzyme 7DHC reductase, and then its spontaneous isomer, 8-dehydrocholesterol (8DHC). Smith-Lemli-Opitz syndrome (SLOS, Mendelian Inheritance in Man #270400) is an autosomal recessive disorder due to an inborn error of cholesterol biosynthesis (Elias et al., 1993; Irons, Elias, Salen, Tint, & Batta, 1993; Tint et al., 1994). Smith-Lemli-Opitz syndrome has an estimated incidence among individuals of European ancestry in Canada and the United States of 1 in 15,000 to 1 in 60,000 births (Bzdúch, Behulova, & Skodova, 2000; Lowry & Yong, 1980; Opitz, 1999; Ryan, Bartlett, Clayton, Eaton, Mills, Donnai, & Burn, 1998) and a carrier frequency of 1 in 30 to 1 in 50 (Nowaczyk & Waye, 2001).

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