title: Mutations in the latent TGF-beta binding protein 3 (LTBP3) gene cause brachyolmia with amelogenesis imperfecta.
abstract: Inherited dental malformations constitute a clinically and genetically heterogeneous group of disorders. Here, we report on four families, three of them consanguineous, with an identical phenotype, characterized by significant short stature with brachyolmia and hypoplastic amelogenesis imperfecta (AI) with almost absent enamel. This phenotype was first described in 1996 by Verloes et al. as an autosomal recessive form of brachyolmia associated with AI. Whole-exome sequencing resulted in the identification of recessive hypomorphic mutations including deletion, nonsense and splice mutations, in the LTBP3 gene, which is involved in the TGF-beta signaling pathway. We further investigated gene expression during mouse development and tooth formation. Differentiated ameloblasts synthesizing enamel matrix proteins and odontoblasts expressed the gene. Study of an available knockout mouse model showed that the mutant mice displayed very thin to absent enamel in both incisors and molars, hereby recapitulating the AI phenotype in the human disorder.
authors: Université de Strasbourg, Laboratoire de Génétique Médicale, INSERM UMR 1112, Faculté de Médecine, FMTS, 11 rue Humann 67000 Strasbourg, France Université de Strasbourg, Faculté de Chirurgie Dentaire, 8 rue St Elisabeth, 67000 Strasbourg, France Hôpitaux Universitaires de Strasbourg, Pôle de Médecine et Chirurgie Bucco-Dentaires, Reference Centre for Orodental Manifestations of Rare Diseases, CRMR, 1 place de l'Hôpital, 67000 Strasbourg, France.
authors: Mathilde
authors: M
authors: Huckert
authors: Université de Strasbourg, Laboratoire de Génétique Médicale, INSERM UMR 1112, Faculté de Médecine, FMTS, 11 rue Humann 67000 Strasbourg, France.
authors: Corinne
authors: C
authors: Stoetzel
authors: Université de Strasbourg, Faculté de Chirurgie Dentaire, 8 rue St Elisabeth, 67000 Strasbourg, France Université de Strasbourg, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CERBM, INSERM U 964, CNRS UMR 7104, 1 rue Laurent Fries, BP 10142, Illkirch 67404, France Faculty of Dentistry, Khon Kaen University, Khon Kaen, Thailand.
authors: Supawich
authors: S
authors: Morkmued
authors: Université de Strasbourg, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CERBM, INSERM U 964, CNRS UMR 7104, 1 rue Laurent Fries, BP 10142, Illkirch 67404, France.
authors: Virginie
authors: V
authors: Laugel-Haushalter
authors: Université de Strasbourg, Laboratoire de Génétique Médicale, INSERM UMR 1112, Faculté de Médecine, FMTS, 11 rue Humann 67000 Strasbourg, France.
authors: Véronique
authors: V
authors: Geoffroy
authors: Université de Strasbourg, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CERBM, INSERM U 964, CNRS UMR 7104, 1 rue Laurent Fries, BP 10142, Illkirch 67404, France Université de Strasbourg, Laboratoire ICube UMR 7357, CNRS, LBGI, Strasbourg, France Hôpitaux Universitaires de Strasbourg, Laboratoire de Diagnostic Génétique, 1 place de l'Hôpital, 67000 Strasbourg, France.
authors: Jean
authors: J
authors: Muller
authors: Université de Strasbourg, Faculté de Chirurgie Dentaire, 8 rue St Elisabeth, 67000 Strasbourg, France Université de Strasbourg, Osteoarticular and Dental Regenerative NanoMedicine, Inserm UMR 1109, 11 rue Humann 67000 Strasbourg, France Hôpitaux Universitaires de Strasbourg, Pôle de Médecine et Chirurgie Bucco-Dentaires, Reference Centre for Orodental Manifestations of Rare Diseases, CRMR, 1 place de l'Hôpital, 67000 Strasbourg, France.
authors: François
authors: F
authors: Clauss
authors: Université de Strasbourg, Laboratoire de Génétique Médicale, INSERM UMR 1112, Faculté de Médecine, FMTS, 11 rue Humann 67000 Strasbourg, France.
authors: Megana K
authors: MK
authors: Prasad
authors: Université de Strasbourg, Faculté de Chirurgie Dentaire, 8 rue St Elisabeth, 67000 Strasbourg, France Hôpitaux Universitaires de Strasbourg, Pôle de Médecine et Chirurgie Bucco-Dentaires, Reference Centre for Orodental Manifestations of Rare Diseases, CRMR, 1 place de l'Hôpital, 67000 Strasbourg, France.
authors: Frédéric
authors: F
authors: Obry
authors: Université de Strasbourg, Faculté de Chirurgie Dentaire, 8 rue St Elisabeth, 67000 Strasbourg, France.
authors: Jean Louis
authors: JL
authors: Raymond
authors: Université de Strasbourg, Faculté de Chirurgie Dentaire, 8 rue St Elisabeth, 67000 Strasbourg, France Hôpitaux Universitaires de Strasbourg, Pôle de Médecine et Chirurgie Bucco-Dentaires, Reference Centre for Orodental Manifestations of Rare Diseases, CRMR, 1 place de l'Hôpital, 67000 Strasbourg, France.
authors: Marzena
authors: M
authors: Switala
authors: Hôpitaux Universitaires de Strasbourg, Service de Génétique Médicale, 1 place de l'Hôpital, 67000 Strasbourg, France.
authors: Yves
authors: Y
authors: Alembik
authors: Hôpitaux Universitaires de Strasbourg, Service de Pédiatrie 1, Endocrinologie Pédiatrique, 1 place de l'Hôpital, 67000 Strasbourg, France.
authors: Sylvie
authors: S
authors: Soskin
authors: Université de Strasbourg, Biomaterials and Bioengineering, Inserm UMR 1121, 11 rue Humann, 67000 Strasbourg, France.
authors: Eric
authors: E
authors: Mathieu
authors: Université de Strasbourg, Biomaterials and Bioengineering, Inserm UMR 1121, 11 rue Humann, 67000 Strasbourg, France.
authors: Joseph
authors: J
authors: Hemmerlé
authors: Université de Strasbourg, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CERBM, INSERM U 964, CNRS UMR 7104, 1 rue Laurent Fries, BP 10142, Illkirch 67404, France.
authors: Jean-Luc
authors: JL
authors: Weickert
authors: Department of Cell Biology, NYU Langone Medical Centre, New York, USA.
authors: Branka Brukner
authors: BB
authors: Dabovic
authors: Department of Cell Biology, NYU Langone Medical Centre, New York, USA.
authors: Daniel B
authors: DB
authors: Rifkin
authors: Center for Medical Genetics, Ghent University, Ghent University Hospital, De Pintelaan 185, Ghent 9000, Belgium.
authors: Annelies
authors: A
authors: Dheedene
authors: Department of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, Edegem 2650, Belgium.
authors: Eveline
authors: E
authors: Boudin
authors: Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Calgary, Alberta Children's Hospital, Calgary, AB, Canada.
authors: Oana
authors: O
authors: Caluseriu
authors: Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Calgary, Alberta Children's Hospital, Calgary, AB, Canada.
authors: Marie-Claude
authors: MC
authors: Cholette
authors: Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Calgary, Alberta Children's Hospital, Calgary, AB, Canada.
authors: Ross
authors: R
authors: Mcleod
authors: Dentistry Division, HC/FMUSP, São Paulo, Brazil.
authors: Reynaldo
authors: R
authors: Antequera
authors: Faculté d'Odontologie, Université de Reims Champagne-Ardenne, 2 rue du Général Koenig, Reims 51100, France Laboratoire EA 4691 'BIOS', 1, rue du Maréchal Juin, Reims 51100, France.
authors: Marie-Paule
authors: MP
authors: Gellé
authors: Faculté d'Odontologie, Université de Reims Champagne-Ardenne, 2 rue du Général Koenig, Reims 51100, France.
authors: Jean-Louis
authors: JL
authors: Coeuriot
authors: Faculté d'Odontologie, Université de Reims Champagne-Ardenne, 2 rue du Général Koenig, Reims 51100, France.
authors: Louis-Frédéric
authors: LF
authors: Jacquelin
authors: Faculty of Dentistry, Paul Sabatier University, LU51, Pôle Odontologie, Hôpitaux de Toulouse, 3 Chemin des Maraîchers, Toulouse, France.
authors: Isabelle
authors: I
authors: Bailleul-Forestier
authors: Université de Strasbourg, Faculté de Chirurgie Dentaire, 8 rue St Elisabeth, 67000 Strasbourg, France Hôpitaux Universitaires de Strasbourg, Pôle de Médecine et Chirurgie Bucco-Dentaires, Reference Centre for Orodental Manifestations of Rare Diseases, CRMR, 1 place de l'Hôpital, 67000 Strasbourg, France.
authors: Marie-Cécile
authors: MC
authors: Manière
authors: Department of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, Edegem 2650, Belgium.
authors: Wim
authors: W
authors: Van Hul
authors: Unidade de Genética do Instituto da Criança, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil and.
authors: Debora
authors: D
authors: Bertola
authors: Université de Strasbourg, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CERBM, INSERM U 964, CNRS UMR 7104, 1 rue Laurent Fries, BP 10142, Illkirch 67404, France.
authors: Pascal
authors: P
authors: Dollé
authors: Département de Génétique - Hôpital Robert Debré, CRMR 'Anomalies du Développement & Syndromes Malformatifs', CRMR 'Déficiences Intellectuelles de Causes Rares', 48 bd Sérurier, Paris 75019, France.
authors: Alain
authors: A
authors: Verloes
authors: Center for Medical Genetics, Ghent University, Ghent University Hospital, De Pintelaan 185, Ghent 9000, Belgium Department of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, Edegem 2650, Belgium.
authors: Geert
authors: G
authors: Mortier
authors: Université de Strasbourg, Laboratoire de Génétique Médicale, INSERM UMR 1112, Faculté de Médecine, FMTS, 11 rue Humann 67000 Strasbourg, France Hôpitaux Universitaires de Strasbourg, Service de Génétique Médicale, 1 place de l'Hôpital, 67000 Strasbourg, France.
authors: Hélène
authors: H
authors: Dollfus
authors: Université de Strasbourg, Laboratoire de Génétique Médicale, INSERM UMR 1112, Faculté de Médecine, FMTS, 11 rue Humann 67000 Strasbourg, France Université de Strasbourg, Laboratoire de Génétique Médicale, INSERM UMR 1112, Faculté de Médecine, FMTS, 11 rue Humann 67000 Strasbourg, France Université de Strasbourg, Laboratoire de Génétique Médicale, INSERM UMR 1112, Faculté de Médecine, FMTS, 11 rue Humann 67000 Strasbourg, France agnes.bloch-zupan@unistra.fr.
authors: Agnès
authors: A
authors: Bloch-Zupan
mesh_terms: D000293:Adolescent; D000567:Amelogenesis Imperfecta / Q000000981:diagnostic imaging / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D002648:Child; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation; D056726:Genetic Association Studies; D006801:Humans; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020125:Mutation, Missense; D010009:Osteochondrodysplasias / Q000000981:diagnostic imaging / Q000235:genetics*; D010375:Pedigree; D011859:Radiography; D017384:Sequence Deletion
chemical_list: C509038:LTBP3 protein, human; D053779:Latent TGF-beta Binding Proteins