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

Correa-Cerro, Lina S.; Porter, Forbes D.

doi:10.1016/j.ymgme.2004.09.017

Cited by 86 publications

(68 citation statements)

References 130 publications

(153 reference statements)

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“…There was some agreement, however; seven TM segments were predicted in nearly identical positions by all the An additional feature associated with cholesterol homeostasis, named "sterol-sensing domain (SSD)" has been identified in a number of proteins, including DHCR7 and HMG Co-A reductase (HMGCR). [120][121][122][123] The SSD is highly conserved with representatives found ranging from humans to nematodes. The consensus topology is described as consisting of ∼180 amino acids organized into a cluster of five consecutive TM domains.…”

Section: Lbr Polypeptide Conformations and Conserved Domainsmentioning

confidence: 99%

“…Examining a ClustalW pairwise alignment of human HMGCR with human LBR indicated that the putative HMGCR SSD region (residues 57-230) did not align with the C-terminus of human LBR (data not shown). However, a potential SSD of human DHCR7, 120 spans residues 181-362, encompassing Sterol Reductase Family Signature 1. Comparing the aligned human DHCR7 and human LBR (Fig.…”

Section: Lbr Polypeptide Conformations and Conserved Domainsmentioning

confidence: 99%

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Lamin B receptor

Olins

Rhodes²,

Welch³

et al. 2010

Nucleus

134

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Section: Lbr Polypeptide Conformations and Conserved Domainsmentioning

confidence: 99%

Section: Lbr Polypeptide Conformations and Conserved Domainsmentioning

confidence: 99%

Lamin B receptor

Olins

Rhodes²,

Welch³

et al. 2010

Nucleus

134

View full text Add to dashboard Cite

“…Battaile and Steiner, 2000;Porter, 2000;Kelly, 2000;Nowaczyk and Waye, 2001;Jira et al, 2003). SLOS arises from mutations in a gene (Dhcr7) that encodes a key enzyme in the cholesterol biosynthesis pathway, namely 3β-hydroxysterol-Δ 7 -reductase (DHCR7) (Waterham and Wanders, 2000;Correa-Cerro and Porter, 2005). A hallmark of SLOS is the abnormal and excessive accumulation of 7-dehydrocholesterol (7DHC), an immediate precursor of cholesterol (Tint et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Light-induced exacerbation of retinal degeneration in a rat model of Smith–Lemli–Opitz syndrome

Vaughan

Peachey

Richards

et al. 2006

Experimental Eye Research

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Potentiation of retinal degeneration by intense light exposure, and its amelioration by an antioxidant, were studied in a rat model of Smith-Lemli-Opitz syndrome (SLOS), in comparison with normal (control) Sprague-Dawley rats. The SLOS model is created by treating rats with AY9944, a selective inhibitor of cholesterol synthesis at the level of 3β-hydroxysterol-Δ 7 -reductase. A subset of rats was treated with dimethylthiourea (DMTU), a synthetic antioxidant, 24 and 1 hr prior to light exposure. Half of the animals (±DMTU) were exposed to intense, constant, green light (24 hr, 1700 lx, 490-580 nm), while the others were maintained in darkness. Subsequently all animals were returned to dim cyclic light (20-40 lx, 12 hr light-12 hr dark) for 2 weeks, after which electroretinograms were recorded. One eye from each rat was taken for histological and quantitative morphometric analyses; sterol analysis was performed on retinas from contralateral eyes. HPLC analysis confirmed the accumulation of 7-dehydrocholesterol (7DHC) in retinas of AY9944-treated rats; cholesterol represented >99% of the sterol in control retinas. Histology of retinas from unexposed, AY9944-treated rats (6-week-old) was normal. In contrast, age-matched, light-exposed rats exhibited massive photoreceptor cell loss in both the superior and inferior hemispheres, and concomitant rod and cone dysfunction. The severity and geographic extent of the damage was far greater than that observed in normal albino rats exposed to the same conditions. DMTU pre-treatment largely prevented these degenerative changes. These findings indicate that the AY9944-induced rat SLOS model is hypersensitive to intense light-induced retinal damage, relative to normal rats. DMTU protection against light-induced damage implicates free radical-based oxidation in the retinal degeneration process. Furthermore, the use of green light (corresponding to the absorption maxima of rhodopsin) implicates rhodopsin in the initiation of the pathobiological mechanism. We propose that generation of cytotoxic oxysterols (by-products of 7DHC oxidation) is an integral part of retinal cell death in the SLOS rat model, which is exacerbated by intense light. Furthermore, the results predict lightdependent potentiation of retinal degeneration in SLOS patients, and the possible ameliorative effects of antioxidant therapy.

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“…Porter, 2000;Jira et al, 2003), is also the first member of a growing family of inborn errors of anabolic metabolism involving defective cholesterol biosynthesis (Kelley, 2000;Porter, 2003). SLOS specifically is due to a defect in 3β-hydroxysterol-Δ 7 -reductase (Waterham and Wanders, 2000;Correa-Cerro and Porter, 2005), resulting in abnormal and excessive accumulation of the cholesterol precursor, 7-dehydrocholesterol (7DHC) (Tint et al, 1994 cf. Fliesler, 2002).…”

mentioning

confidence: 99%

Lipid hydroperoxide formation in the retina: correlation with retinal degeneration and light damage in a rat model of Smith–Lemli–Opitz syndrome

Richards

Nagel

Fliesler

2006

Experimental Eye Research

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The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disease presenting with multiple congenital anomalies, caused by a defect in cholesterol biosynthesis that results in abnormally elevated levels of 7-dehydrocholesterol (7DHC). Progressive retinal degeneration has been demonstrated in a rat model of SLOS, which is markedly exacerbated by intense light, far more so than occurs in normal albino rats under the same conditions. Herein, we demonstrate that, by six postnatal weeks, retinas in the SLOS rat model contain levels of lipid hydroperoxides (LPOs) comparable to those found in light-damaged albino rats (twice the normal steady-state levels), and that intense light exposure results in a three-fold elevation of LPOs with concomitant severe retinal degeneration. These results suggest a correlation between retinal degeneration and LPO levels. We propose that the presence of 7DHC in the SLOS rat retina potentiates LPO formation, and promotes the observed hypersensitivity to light-induced retinal degeneration. KeywordsAY9944; Smith-Lemli-Opitz syndrome; retina; degeneration; light damage; lipid hydroperoxide; rat Retinal degenerations resulting either from hereditary or exogenous causes are thought to entail molecular events that, in part, involve oxidative damage to lipids, proteins, and/or nucleic acids, resulting in cellular dysfunction and, ultimately, cell death. Such events are known to be potentiated by exposure to intense light (Organisciak and Winkler, 1994;Boulton et al., 2001;Glickman, 2002;Wenzel et al., 2005). Certain metabolic conditions result in the formation of pro-oxidant molecules, the presence of which can promote cellular degeneration and death. The Smith-Lemli-Opitz syndrome (SLOS) likely represents such a condition. SLOS, the first described 'multiple congenital anomalies syndrome ' (Smith et al., 1964; cf. Porter, 2000;Jira et al., 2003), is also the first member of a growing family of inborn errors of anabolic metabolism involving defective cholesterol biosynthesis (Kelley, 2000;Porter, 2003). SLOS specifically is due to a defect in 3β-hydroxysterol-Δ 7 -reductase (Waterham and Wanders, 2000;Correa-Cerro and Porter, 2005), resulting in abnormal and excessive accumulation of the cholesterol precursor, 7-dehydrocholesterol (7DHC) (Tint et al., 1994 cf. Fliesler, 2002).We have previously demonstrated a progressive retinal degeneration in a pharmacologically induced rat model of SLOS (Fliesler et al., 2004). More recently, we showed that intense light exposure markedly exacerbates that retinal degeneration, whereas treatment of rats with dimethylthiourea, a hydroxyl radical scavenger and anti-oxidant, prior to light exposure largely protects against the enhancement of degeneration (Vaughan et al., 2005), implicating a free radical mechanism in the degeneration. Herein, we provide evidence that correlates the severity of retinal degeneration in the SLOS rat model, relative to normal albino rats, with accumulated levels of lipid hydroxperoxides (LPOs) in the retina, particu...

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

Cited by 86 publications

References 130 publications

Lamin B receptor

Lamin B receptor

Light-induced exacerbation of retinal degeneration in a rat model of Smith–Lemli–Opitz syndrome

Lipid hydroperoxide formation in the retina: correlation with retinal degeneration and light damage in a rat model of Smith–Lemli–Opitz syndrome

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