Aideen M McInerney-Leo1, Carine Le Goff2, Paul J Leo1, Tony J Kenna1, Patricia Keith1, Jessica E Harris1, Ruth Steer3, Christine Bole-Feysot4, Patrick Nitschke5, Cay Kielty3, Matthew A Brown1, Andreas Zankl6, Emma L Duncan7, Valerie Cormier-Daire2. 1. 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. 2. 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. 3. Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK. 4. Plateforme de Génomique, Fondation IMAGINE, Paris, France. 5. Plateforme de Bioinformatique, Université Paris Descartes, Paris, France. 6. 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. 7. 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.
Abstract
BACKGROUND: 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. METHODS: Individuals negative for mutations in known acromelic dysplasia genes underwent whole exome sequencing. RESULTS: 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). CONCLUSIONS: 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
BACKGROUND: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. METHODS: Individuals negative for mutations in known acromelic dysplasia genes underwent whole exome sequencing. RESULTS: 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). CONCLUSIONS: 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 ltbp3mice phenotype. We conclude that LTBP3 is a novel component of the microfibrillar network involved in the acromelic dysplasia spectrum. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Authors: R A Packer; M A Logan; L T Guo; S S Apte; H Bader; D P O'Brien; G Johnson; G D Shelton Journal: J Vet Intern Med Date: 2017-02-03 Impact factor: 3.333
Authors: Pasquale Piccolo; Valeria Sabatino; Pratibha Mithbaokar; Elena Polishchuk; John Hicks; Roman Polishchuk; Carlos A Bacino; Nicola Brunetti-Pierri Journal: Mol Genet Genomic Med Date: 2019-07-27 Impact factor: 2.183