title: Involvement and alteration of the Sonic Hedgehog pathway is associated with decreased cholesterol level in trisomy 18 and SLO amniocytes.
abstract: BACKGROUND
  Trisomy 18 and Smith-Lemli-Opitz syndrome are two polymalformative conditions in which a cholesterol defect has been noted. When they occur prenatally, they are associated with a decreased maternal unconjugated estriol (uE(3)) level. Cholesterol plays an essential role in the Sonic Hedgehog pathway, allowing Shh protein maturation leading to its maximal activity. Many malformations in these two syndromes occur in Shh dependent tissues. We thus sought to assess whether a cholesterol defect could affect the Shh pathway and explain some of the observed malformations.
  
  
  METHODS
  We selected 14 cases of trisomy 18 and 3 cases of SLO in which the maternal uE(3) level was decreased and reported malformations were observed after fetopathological examination. We correlated the number of malformations with maternal uE(3) level. We then carried out cholesterol concentrations in separate culture media consisting of trisomy 18, SLO and control amniocytes. Finally, we analyzed the Shh pathway by testing the gene expression of several Shh components: GLI transcription factors, BMP2, BMP4, TGFβ1, COL1A1 and COL1A2.
  
  
  CONCLUSIONS
  There was an inverse correlation between phenotypic severity and maternal uE(3) levels in SLO and trisomy 18. The cholesterol levels in the amniocyte culture media were correlated with maternal uE3 levels and were significantly lower in T18 and SLO amniocytes, reflecting cholesterol defects. There was an alteration in the Shh pathway since expression of several genes was decreased in T18 and SLO amniocytes. However, these cholesterol defects were not solely responsible for the altered Shh pathway and the malformations observed.
authors.affiliation: Laboratoire de cytogénétique prénatale, service de Génétique, avenue Côte de Nacre, CHU Caen, UFR médecine, 14033 Caen cedex 9, France. Electronic address: gruchy-n@chu-caen.fr.
authors.forename: N
authors.initials: N
authors.lastname: Gruchy
authors.affiliation: Laboratoire "Microenvironnement cellulaire et pathologie" (MILPAT) EA 4652, UFR Médecine Caen, avenue Côte de Nacre, 14033 Caen cedex 9, France. Electronic address: nicolas.bigot@hotmail.fr.
authors.forename: N
authors.initials: N
authors.lastname: Bigot
authors.affiliation: Service d'Anatomie pathologique, CHU Caen, UFR Médecine, 14033 Caen cedex 9, France. Electronic address: jeannepasquier-c@chu-caen.fr.
authors.forename: C
authors.initials: C
authors.lastname: Jeanne Pasquier
authors.affiliation: Service de biochimie métabolique, CHU Caen, UFR Médecine, 14033 Caen cedex 9, France. Electronic address: read-mh@chu-caen.fr.
authors.forename: M H
authors.initials: MH
authors.lastname: Read
authors.affiliation: Génétique des pathologies liées au développement, CNRS, UMR6290, UFR Médecine, Rennes, France. Electronic address: sylvie.odent@chu-rennes.fr.
authors.forename: S
authors.initials: S
authors.lastname: Odent
authors.affiliation: Laboratoire "Microenvironnement cellulaire et pathologie" (MILPAT) EA 4652, UFR Médecine Caen, avenue Côte de Nacre, 14033 Caen cedex 9, France. Electronic address: philippe.galera@unicaen.fr.
authors.forename: P
authors.initials: P
authors.lastname: Galera
authors.affiliation: Laboratoire de cytogénétique prénatale, service de Génétique, avenue Côte de Nacre, CHU Caen, UFR médecine, 14033 Caen cedex 9, France. Electronic address: leporrier-n@chu-caen.fr.
authors.forename: N
authors.initials: N
authors.lastname: Leporrier
mesh_terms: D000653:Amniotic Fluid / Q000378:metabolism; D000069059:Atorvastatin; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D002887:Chromosomes, Human, Pair 18 / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D000090602:Collagen Type I, alpha 1 Chain; D003470:Culture Media / Q000737:chemistry; D004964:Estriol / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D011247:Pregnancy; D011758:Pyrroles / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D019082:Smith-Lemli-Opitz Syndrome / Q000378:metabolism / Q000473:pathology*; D014314:Trisomy / Q000473:pathology*; D000073842:Trisomy 18 Syndrome
chemical_list: D055396:Bone Morphogenetic Protein 2; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D003470:Culture Media; D053823:Hedgehog Proteins; D006538:Heptanoic Acids; D011758:Pyrroles; C509239:SHH protein, human; D002784:Cholesterol; D000069059:Atorvastatin; D004964:Estriol
keywords: Cholesterol; Smith–Lemli–Opitz syndrome; Sonic Hedgehog; Trisomy 18