Defective cholesterol biosynthesis in Smith-Lemli-Opitz syndrome

Irons, Mira; Elias, Ellen Roy; Salen, Gerald; Tint, G. S.; Batta, AshokK.

doi:10.1016/0140-6736(93)90983-n

Cited by 367 publications

(243 citation statements)

References 3 publications

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“…Nevertheless, 7DHC is the prominent sterol in the SLOS membrane and the biophysical parameters of Kv1.3 gating were similarly affected in SLOS and in T cells treated with MβCD/7DHC complex. This suggests that acute loading of T cells with 7DHC mimics adequately the effect of the lipid milieu existing in SLOS on the operation of Kv1.3 [11,29,30,54,68].…”

Section: Discussionmentioning

confidence: 84%

“…In the last decades, numerous malformation syndromes have been associated with the inborn error of the CHOL synthesis (reviewed in [46]). The link between reduced CHOL synthesis and a serious health condition was described first for the Smith-LemliOpitz syndrome (SLOS) [29,59,65]. The SLOS phenotypic spectrum is very broad, ranging from a mild disorder with behavioral and learning problems to a lethal malformation syndrome (incidence of SLOS is 1 in 39,000 births [17]) [45,46].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, many SLOS infants have behaviour problems (autism, hyperactivity, self-injures behavior) [45,46]. Irons and his colleagues showed that the SLOS is caused by the deficiency of 7-dehyrocholesterol-reductase (DHCR7), which catalyzes the last step in the CHOL biosynthetic pathway [29]. Altered DHCR7 activity led to increased 7DHC and reduced CHOL levels both in the serum and in the plasma membrane of fibroblasts and erythrocytes [16,61].The severity of the disease and life expectancy of the patients is mostly determined by initial serum CHOL level, while the ratio of 7DHC/CHOL has an additional prognostic value [5].…”

Section: Introductionmentioning

confidence: 99%

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7DHC-induced changes of Kv1.3 operation contributes to modified T cell function in Smith-Lemli-Opitz syndrome

Balajthy

Somodi

Pethő

et al. 2016

Pflugers Arch - Eur J Physiol

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In vitro manipulation of membrane sterol level affects the regulation of ion channels and consequently certain cellular functions; however, a comprehensive study that confirms the pathophysiological significance of these results is missing. The malfunction of 7-dehydrocholesterol (7DHC) reductase in Smith-Lemli-Opitz syndrome (SLOS) leads to the elevation of the 7-dehydrocholesterol level in the plasma membrane. T lymphocytes were isolated from SLOS patients to assess the effect of the in vivo altered membrane sterol composition on the operation of the voltage-gated Kv1.3 channel and the ion channel-dependent mitogenic responses. We found that the kinetic and equilibrium parameters of Kv1.3 activation changed in SLOS cells. Identical changes in Kv1.3 operation were observed when control/healthy T cells were loaded with 7DHC. Removal of the putative sterol binding sites on Kv1.3 resulted in a phenotype that was not influenced by the elevation in membrane sterol level. Functional assays exhibited impaired activation and proliferation rate of T cells probably partially due to the modified Kv1.3 operation. We concluded that the altered membrane sterol composition hindered the operation of Kv1.3 as well as the ion channel-controlled T cell functions.

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Section: Discussionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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7DHC-induced changes of Kv1.3 operation contributes to modified T cell function in Smith-Lemli-Opitz syndrome

Balajthy

Somodi

Pethő

et al. 2016

Pflugers Arch - Eur J Physiol

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“…SLO is an autosomal-recessive disorder due to mutations in the gene for D7-dehydrocholesterol reductase, 63,64 leading to increased serum levels of 7-dehydrocholesterol. The incidence has been estimated to be one in 10 000 to one in 60 000.…”

Section: Single Gene Disorders Associated With Admentioning

confidence: 99%

The genetics of autistic disorders and its clinical relevance: a review of the literature

2006

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Twin and family studies in autistic disorders (AD) have elucidated a high heritability of the narrow and broad phenotype of AD. In this review on the genetics of AD, we will initially delineate the phenotype of AD and discuss aspects of differential diagnosis, which are particularly relevant with regard to the genetics of autism. Cytogenetic and molecular genetic studies will be presented in detail, and the possibly involved aetiopathological pathways will be described. Implications of the different genetic findings for genetic counselling will be mentioned.

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“…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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Defective cholesterol biosynthesis in Smith-Lemli-Opitz syndrome

Cited by 367 publications

References 3 publications

7DHC-induced changes of Kv1.3 operation contributes to modified T cell function in Smith-Lemli-Opitz syndrome

7DHC-induced changes of Kv1.3 operation contributes to modified T cell function in Smith-Lemli-Opitz syndrome

The genetics of autistic disorders and its clinical relevance: a review of the literature

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

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