Maternal apo E genotype is a modifier of the Smith-Lemli-Opitz syndrome

Witsch‐Baumgartner, Martina; Gruber, Mijail; Kraft, H. G.; Rossi, Massimiliano; Clayton, Peter T.; Girós, M.; Haas, Dorothea; Kelley, Richard I.; Krajewska‐Walasek, M; Utermann, Gerd

doi:10.1136/jmg.2004.018085

Cited by 79 publications

(63 citation statements)

References 35 publications

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“…In addition, activity of sonic hedgehog (SHH) proteins, which are responsible for the development of the central nervous system (13)(14)(15), is determined by covalent modification with cholesterol and other lipids (16). During organogenesis, the embryo is reliant on maternal sources of cholesterol until its liver is sufficiently mature for synthesis (4,17). Our data show that the human yolk sac contains abundant mRNAs encoding multiple apolipoproteins, the cholesterol efflux transporter ABCA1, and lipoprotein receptors, including megalin and cubilin (18), albeit at lower levels (Fig.…”

Section: Significancementioning

confidence: 99%

RNA-seq reveals conservation of function among the yolk sacs of human, mouse, and chicken

Cindrová‐Davies

Jauniaux

Elliot

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The yolk sac is phylogenetically the oldest of the extraembryonic membranes. The human embryo retains a yolk sac, which goes through primary and secondary phases of development, but its importance is controversial. Although it is known to synthesize proteins, its transport functions are widely considered vestigial. Here, we report RNA-sequencing (RNA-seq) data for the human and murine yolk sacs and compare those data with data for the chicken. We also relate the human RNA-seq data to proteomic data for the coelomic fluid bathing the yolk sac. Conservation of transcriptomes across the species indicates that the human secondary yolk sac likely performs key functions early in development, particularly uptake and processing of macro-and micronutrients, many of which are found in coelomic fluid. More generally, our findings shed light on evolutionary mechanisms that give rise to complex structures such as the placenta. We identify genetic modules that are conserved across mammals and birds, suggesting these modules are part of the core amniote genetic repertoire and are the building blocks for both oviparous and viviparous reproductive modes. We propose that although a choriovitelline placenta is never established physically in the human, the placental villi, the exocoelomic cavity, and the secondary yolk sac function together as a physiological equivalent.yolk sac | placenta | evolution

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Section: Significancementioning

confidence: 99%

RNA-seq reveals conservation of function among the yolk sacs of human, mouse, and chicken

Cindrová‐Davies

Jauniaux

Elliot

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Maternal, but not fetal, APOE2 allele genotype was associated with a poorer clinical severity score. However, in one case, where the mother was homozygous for APOE2, severity score of the patient was lower, suggesting this effect is not dose dependent [11]. Additionally, given the significant possible errors that can occur when the sample size used in genetic polymorphism association studies is low [31,32], the role of maternal APOE status affecting clinical severity in SLOS should be regarded as probable, but not proven [32].…”

Section: Discussionmentioning

confidence: 99%

“…One candidate is therefore the APOE locus, either by its effects directly in the developing fetus, on fetal lipoprotein metabolism, or by affecting maternal cholesterol levels and materno-fetal lipoprotein metabolism [19,20]. A recent study has implicated maternal APOE variations as determinants of severity in SLOS [11]. Maternal, but not fetal, APOE2 allele genotype was associated with a poorer clinical severity score.…”

Section: Discussionmentioning

confidence: 99%

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Loss of apolipoprotein E exacerbates the neonatal lethality of the Smith-Lemli-Opitz syndrome mouse

Solcà

Pandit

et al. 2007

Molecular Genetics and Metabolism

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The Smith-Lemli-Opitz syndrome (SLOS) is caused by a genetic defect in cholesterol biosynthesis; mutations in the enzyme 3ß-hydroxysterol Δ7 reductase (Dhcr7) lead to a failure of cholesterol (and desmosterol) synthesis, with an accumulation of precursor sterols, such as 7-dehydrocholesterol. Extensive genotype-phenotype analyses have indicated that there is considerable variation in the severity of the disease, much of which is not explained by defects in the Dhcr7 gene alone. Factors ranging from variations in maternal-fetal cholesterol transfer during pregnancy, to other genetic factors have been proposed to account for this variability. Variations at the APOE locus affect plasma cholesterol levels in humans and this polymorphic gene has been found to be associated with cardiovascular as well as neurological disorders. This locus has recently been implicated in accounting for some of the variations in SLOS. To address whether maternal hypercholesterolemia can affect fetal outcome, we tested the ability of maternal hypercholesterolemia to rescue the neonatal lethality in a mouse model of SLOS. Maternal hypercholesterolemia, induced by ApoE or Ldl-r deficiency not only failed to ameliorate the postnatal lethality, it increased the prenatal mortality of Dhcr7 deficient pups. Thus the murine data suggest that maternal loss of ApoE or Ldl-r function further exacerbates the neonatal lethality, suggesting they may play a role in maternal transfer of cholesterol to the embryo.

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“…12 Previous studies have shown a correlation of SLOS severity with DHCR7 genotype and maternal ApoE genotype, but a large part of the clinical variability remains unexplained. 3,13 We have now investigated genes involved in lipid metabolism and transport as candidate modifiers of the clinical severity of SLOS. These include ApoC-III, lecithin-cholesterol acyltransferase (LCAT), cholesteryl-ester transfer protein (CETP), 14 and ATP-binding cassette transporter A1 (ABCA1).…”

Section: Introductionmentioning

confidence: 99%

Maternal ABCA1 genotype is associated with severity of Smith–Lemli–Opitz syndrome and with viability of patients homozygous for null mutations

et al. 2012

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The Smith-Lemli-Opitz syndrome (SLOS [MIM 270400]) is an autosomal recessive malformation syndrome that shows a great variability with regard to severity. SLOS is caused by mutations in the D7sterol-reductase gene (DHCR7), which disrupt cholesterol biosynthesis. Phenotypic variability of the disease is already known to be associated with maternal apolipoprotein E (ApoE) genotype. The aim of this study was to detect additional modifiers of the SLOS phenotype. We examined the association of SLOS severity with variants in the genes for ApoC-III, lecithin-cholesterol acyltransferase, cholesteryl-ester transfer protein, ATP-binding cassette transporter A1 (ABCA1), and methylene tetrahydrofolate reductase. Our study group included 59 SLOS patients, their mothers, and 49 of their fathers. In addition, we investigated whether ApoE and ABCA1 genotypes are associated with the viability of severe SLOS cases (n ¼ 21) caused by two null mutations in the DHCR7 gene. Maternal ABCA1 genotypes show a highly significant correlation with clinical severity in SLOS patients (P ¼ 0.007). The rare maternal p.1587Lys allele in the ABCA1 gene was associated with milder phenotypes. ANOVA analysis demonstrated an association of maternal ABCA1 genotypes with severity scores (logarithmised) of SLOS patients of P ¼ 0.004. Maternal ABCA1 explains 15.4% (R 2 ) of severity of SLOS patients. There was no association between maternal ApoE genotype and survival of the SLOS fetus carrying two null mutations. Regarding ABCA1 p.Arg1587Lys in mothers of latter SLOS cases, a significant deviation from HardyWeinberg equilibrium (HWE) was observed (P ¼ 0.005). ABCA1 is an additional genetic modifier in SLOS. Modifying placental cholesterol transfer pathways may be an approach for prenatal therapy of SLOS.

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Maternal apo E genotype is a modifier of the Smith-Lemli-Opitz syndrome

Cited by 79 publications

References 35 publications

RNA-seq reveals conservation of function among the yolk sacs of human, mouse, and chicken

RNA-seq reveals conservation of function among the yolk sacs of human, mouse, and chicken

Loss of apolipoprotein E exacerbates the neonatal lethality of the Smith-Lemli-Opitz syndrome mouse

Maternal ABCA1 genotype is associated with severity of Smith–Lemli–Opitz syndrome and with viability of patients homozygous for null mutations

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