title: Mutations in LTBP3 cause acromicric dysplasia and geleophysic dysplasia.
abstract: Acromelic dysplasias are a group of disorders characterised by short stature, brachydactyly, limited joint extension and thickened skin and comprises acromicric dysplasia (AD), geleophysic dysplasia (GD), Myhre syndrome and Weill-Marchesani syndrome. Mutations in several genes have been identified for these disorders (including latent transforming growth factor β (TGF-β)-binding protein-2 (LTBP2), ADAMTS10, ADAMSTS17 and fibrillin-1 (FBN1) for Weill-Marchesani syndrome, ADAMTSL2 for recessive GD and FBN1 for AD and dominant GD), encoding proteins involved in the microfibrillar network. However, not all cases have mutations in these genes.
  
  
  
  Individuals negative for mutations in known acromelic dysplasia genes underwent whole exome sequencing.
  
  
  
  A heterozygous missense mutation (exon 14: c.2087C>G: p.Ser696Cys) in latent transforming growth factor β (TGF-β)-binding protein-3 (LTBP3) was identified in a dominant AD family. Two distinct de novo heterozygous LTPB3 mutations were also identified in two unrelated GD individuals who had died in early childhood from respiratory failure-a donor splice site mutation (exon 12 c.1846+5G>A) and a stop-loss mutation (exon 28: c.3912A>T: p.1304*Cysext*12).
  
  
  
  The constellation of features in these AD and GD cases, including postnatal growth retardation of long bones and lung involvement, is reminiscent of the null ltbp3 mice phenotype. We conclude that LTBP3 is a novel component of the microfibrillar network involved in the acromelic dysplasia spectrum.
authors.affiliation: Queensland University of Technology (QUT), Institute of Health and Biomedical Innovation (IHBI), Queensland, Australia The University of Queensland Diamantina Institute, University of Queensland, Queensland, Australia.
authors.forename: Aideen M
authors.initials: AM
authors.lastname: McInerney-Leo
authors.affiliation: Department of Genetics, Reference Center for Skeletal Dysplasia, Paris Descartes University-Sorbonne Paris Cité, INSERM U MR1163, IMAGINE Institute, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Carine
authors.initials: C
authors.lastname: Le Goff
authors.affiliation: Queensland University of Technology (QUT), Institute of Health and Biomedical Innovation (IHBI), Queensland, Australia The University of Queensland Diamantina Institute, University of Queensland, Queensland, Australia.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Leo
authors.affiliation: Queensland University of Technology (QUT), Institute of Health and Biomedical Innovation (IHBI), Queensland, Australia The University of Queensland Diamantina Institute, University of Queensland, Queensland, Australia.
authors.forename: Tony J
authors.initials: TJ
authors.lastname: Kenna
authors.affiliation: Queensland University of Technology (QUT), Institute of Health and Biomedical Innovation (IHBI), Queensland, Australia The University of Queensland Diamantina Institute, University of Queensland, Queensland, Australia.
authors.forename: Patricia
authors.initials: P
authors.lastname: Keith
authors.affiliation: Queensland University of Technology (QUT), Institute of Health and Biomedical Innovation (IHBI), Queensland, Australia The University of Queensland Diamantina Institute, University of Queensland, Queensland, Australia.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Harris
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK.
authors.forename: Ruth
authors.initials: R
authors.lastname: Steer
authors.affiliation: Plateforme de Génomique, Fondation IMAGINE, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Bole-Feysot
authors.affiliation: Plateforme de Bioinformatique, Université Paris Descartes, Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschke
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK.
authors.forename: Cay
authors.initials: C
authors.lastname: Kielty
authors.affiliation: Queensland University of Technology (QUT), Institute of Health and Biomedical Innovation (IHBI), Queensland, Australia The University of Queensland Diamantina Institute, University of Queensland, Queensland, Australia.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
authors.affiliation: Discipline of Genetic Medicine, University of Sydney, Sydney, Australia Academic Department of Medical Genetics, Sydney Children's Hospital Network (Westmead), Sydney, New South Wales, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Zankl
authors.affiliation: Queensland University of Technology (QUT), Institute of Health and Biomedical Innovation (IHBI), Queensland, Australia Department of Endocrinology, James Mayne Building, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia The University of Queensland, University of Queensland Centre for Clinical Research, Herston, Queensland, Australia.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Duncan
authors.affiliation: Department of Genetics, Reference Center for Skeletal Dysplasia, Paris Descartes University-Sorbonne Paris Cité, INSERM U MR1163, IMAGINE Institute, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Cormier-Daire
mesh_terms: D001848:Bone Diseases, Developmental / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005091:Exons / Q000235:genetics; D000071838:Fibrillin-1 / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics*; D017880:Limb Deformities, Congenital / Q000235:genetics*; D008840:Microfilament Proteins / Q000235:genetics; D009154:Mutation; D020125:Mutation, Missense / Q000235:genetics*; D010641:Phenotype; D016212:Transforming Growth Factor beta / Q000235:genetics; D056846:Weill-Marchesani Syndrome / Q000235:genetics
chemical_list: D000071838:Fibrillin-1; C509035:LTBP2 protein, human; C509038:LTBP3 protein, human; D053779:Latent TGF-beta Binding Proteins; D008840:Microfilament Proteins; D016212:Transforming Growth Factor beta
keywords: acromelic dysplasia; acromicric dysplasia; fibrillins; geleophysic dysplasia; latent transforming factor-beta binding proteins (LTBP)