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Bi-allelic Variations of SMO in Humans Cause a Broad Spectrum of Developmental Anomalies Due to Abnormal Hedgehog Signaling.
Le, Thuy-Linh; Sribudiani, Yunia; Dong, Xiaomin; Huber, Céline; Kois, Chelsea; Baujat, Geneviève; Gordon, Christopher T; Mayne, Valerie; Galmiche, Louise; Serre, Valérie; Goudin, Nicolas; Zarhrate, Mohammed; Bole-Feysot, Christine; Masson, Cécile; Nitschké, Patrick; Verheijen, Frans W; Pais, Lynn; Pelet, Anna; Sadedin, Simon; Pugh, John A; Shur, Natasha; White, Susan M; El Chehadeh, Salima; Christodoulou, John; Cormier-Daire, Valérie; Hofstra, R M W; Lyonnet, Stanislas; Tan, Tiong Yang; Attié-Bitach, Tania; Kerstjens-Frederikse, Wilhelmina S; Amiel, Jeanne; Thomas, Sophie.
Afiliación
  • Le TL; Université de Paris, Imagine Institute, Laboratory of Embryology and Genetics of Malformations, INSERM UMR 1163, 75015 Paris, France.
  • Sribudiani Y; Department of Clinical Genetics, Erasmus Medical Center, 3015 GD Rotterdam, the Netherlands; Department of Biomedical Sciences, Division of Biochemistry and Molecular Biology, Faculty of Medicine, Universitas Padjadjaran, Bandung 40132, Indonesia.
  • Dong X; Brain and Mitochondrial Research Group, Murdoch Children's Research Institute, Royal Children's Hospital, 50 Flemington Rd, Parkville VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, 3010 Victoria, Australia.
  • Huber C; Université de Paris, Imagine Institute, Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, INSERM UMR 1163, 75015 Paris, France.
  • Kois C; Albany Medical Center, 43 New Scotland Ave, Albany, NY 12208, USA.
  • Baujat G; Université de Paris, Imagine Institute, Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, INSERM UMR 1163, 75015 Paris, France; Fédération de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, 75015 Paris, France.
  • Gordon CT; Université de Paris, Imagine Institute, Laboratory of Embryology and Genetics of Malformations, INSERM UMR 1163, 75015 Paris, France.
  • Mayne V; Department of Medical Imaging, Royal Children's Hospital, Melbourne, Australia 3052.
  • Galmiche L; Department of Pathology, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, 75015 Paris, France.
  • Serre V; Université de Paris, Institut Jacques Monod, UMR7592 CNRS, 15 Rue Hélène Brion, 75013 Paris, France.
  • Goudin N; Université de Paris, Imagine Institute, Cell Imaging, INSERM UMR 1163, 75015 Paris, France.
  • Zarhrate M; Université de Paris, Imagine Institute, Structure Fédérative de Recherche Necker, Genomic Platform, INSERM UMR 1163 and INSERM US24, Centre National de la Recherche Scientifique UMS3633, 75015 Paris, France.
  • Bole-Feysot C; Université de Paris, Imagine Institute, Structure Fédérative de Recherche Necker, Genomic Platform, INSERM UMR 1163 and INSERM US24, Centre National de la Recherche Scientifique UMS3633, 75015 Paris, France.
  • Masson C; Université de Paris, Imagine Institute, Bioinformatics Platform, INSERM UMR 1163, 75015 Paris, France.
  • Nitschké P; Université de Paris, Imagine Institute, Bioinformatics Platform, INSERM UMR 1163, 75015 Paris, France.
  • Verheijen FW; Department of Clinical Genetics, Erasmus Medical Center, 3015 GD Rotterdam, the Netherlands.
  • Pais L; Center for Mendelian Genomics, Broad Institute of MIT and Harvard, 415 Main St, Cambridge, MA 02142, USA.
  • Pelet A; Université de Paris, Imagine Institute, Laboratory of Embryology and Genetics of Malformations, INSERM UMR 1163, 75015 Paris, France.
  • Sadedin S; Brain and Mitochondrial Research Group, Murdoch Children's Research Institute, Royal Children's Hospital, 50 Flemington Rd, Parkville VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, 3010 Victoria, Australia.
  • Pugh JA; Albany Medical Center, 43 New Scotland Ave, Albany, NY 12208, USA.
  • Shur N; Children's National, 111 Michigan Ave NW, Washington, D.C. 20010, USA.
  • White SM; Victorian Clinical Genetics Services, Murdoch Children's Research Institute and Department of Pediatrics, University of Melbourne, Melbourne, Australia 3052.
  • El Chehadeh S; Service de Génétique Médicale, Hôpital de Hautepierre, 67098 Strasbourg, France.
  • Christodoulou J; Brain and Mitochondrial Research Group, Murdoch Children's Research Institute, Royal Children's Hospital, 50 Flemington Rd, Parkville VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, 3010 Victoria, Australia.
  • Cormier-Daire V; Université de Paris, Imagine Institute, Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, INSERM UMR 1163, 75015 Paris, France; Fédération de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, 75015 Paris, France.
  • Hofstra RMW; Department of Clinical Genetics, Erasmus Medical Center, 3015 GD Rotterdam, the Netherlands.
  • Lyonnet S; Université de Paris, Imagine Institute, Laboratory of Embryology and Genetics of Malformations, INSERM UMR 1163, 75015 Paris, France; Fédération de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, 75015 Paris, France.
  • Tan TY; Victorian Clinical Genetics Services, Murdoch Children's Research Institute and Department of Pediatrics, University of Melbourne, Melbourne, Australia 3052.
  • Attié-Bitach T; Fédération de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, 75015 Paris, France; Université de Paris, Imagine Institute, Laboratory of Genetics and Development of the Cerebral Cortex, INSERM UMR 1163, 75015 Paris, France.
  • Kerstjens-Frederikse WS; Department of Genetics, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands.
  • Amiel J; Université de Paris, Imagine Institute, Laboratory of Embryology and Genetics of Malformations, INSERM UMR 1163, 75015 Paris, France; Fédération de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, 75015 Paris, France.
  • Thomas S; Université de Paris, Imagine Institute, Laboratory of Embryology and Genetics of Malformations, INSERM UMR 1163, 75015 Paris, France. Electronic address: sophie.thomas@inserm.fr.
Am J Hum Genet ; 106(6): 779-792, 2020 06 04.
Article en En | MEDLINE | ID: mdl-32413283
ABSTRACT
The evolutionarily conserved hedgehog (Hh) pathway is essential for organogenesis and plays critical roles in postnatal tissue maintenance and renewal. A unique feature of the vertebrate Hh pathway is that signal transduction requires the primary cilium (PC) where major pathway components are dynamically enriched. These factors include smoothened (SMO) and patched, which constitute the core reception system for sonic hedgehog (SHH) as well as GLI transcription factors, the key mediators of the pathway. Here, we report bi-allelic loss-of-function variations in SMO in seven individuals from five independent families; these variations cause a wide phenotypic spectrum of developmental anomalies affecting the brain (hypothalamic hamartoma and microcephaly), heart (atrioventricular septal defect), skeleton (postaxial polydactyly, narrow chest, and shortening of long bones), and enteric nervous system (aganglionosis). Cells derived from affected individuals showed normal ciliogenesis but severely altered Hh-signal transduction as a result of either altered PC trafficking or abnormal activation of the pathway downstream of SMO. In addition, Hh-independent GLI2 accumulation at the PC tip in cells from the affected individuals suggests a potential function of SMO in regulating basal ciliary trafficking of GLI2 when the pathway is off. Thus, loss of SMO function results in abnormal PC dynamics of key components of the Hh signaling pathway and leads to a large continuum of malformations in humans.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Discapacidades del Desarrollo / Alelos / Proteínas Hedgehog / Receptor Smoothened Límite: Child / Child, preschool / Female / Humans / Infant / Male Idioma: En Revista: Am J Hum Genet Año: 2020 Tipo del documento: Article País de afiliación: Francia
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Discapacidades del Desarrollo / Alelos / Proteínas Hedgehog / Receptor Smoothened Límite: Child / Child, preschool / Female / Humans / Infant / Male Idioma: En Revista: Am J Hum Genet Año: 2020 Tipo del documento: Article País de afiliación: Francia