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Mutations in LTBP3 cause acromicric dysplasia and geleophysic dysplasia
  1. Aideen M McInerney-Leo1,2,
  2. Carine Le Goff3,
  3. Paul J Leo1,2,
  4. Tony J Kenna1,2,
  5. Patricia Keith1,2,
  6. Jessica E Harris1,2,
  7. Ruth Steer4,
  8. Christine Bole-Feysot5,
  9. Patrick Nitschke6,
  10. Cay Kielty4,
  11. Matthew A Brown1,2,
  12. Andreas Zankl7,8,
  13. Emma L Duncan1,9,10,
  14. Valerie Cormier-Daire3
  1. 1Queensland University of Technology (QUT), Institute of Health and Biomedical Innovation (IHBI), Queensland, Australia
  2. 2The University of Queensland Diamantina Institute, University of Queensland, Queensland, Australia
  3. 3Department of Genetics, Reference Center for Skeletal Dysplasia, Paris Descartes University-Sorbonne Paris Cité, INSERM U MR1163, IMAGINE Institute, Hôpital Necker-Enfants Malades, Paris, France
  4. 4Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK
  5. 5Plateforme de Génomique, Fondation IMAGINE, Paris, France
  6. 6Plateforme de Bioinformatique, Université Paris Descartes, Paris, France
  7. 7Discipline of Genetic Medicine, University of Sydney, Sydney, Australia
  8. 8Academic Department of Medical Genetics, Sydney Children's Hospital Network (Westmead), Sydney, New South Wales, Australia
  9. 9Department of Endocrinology, James Mayne Building, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia
  10. 10The University of Queensland, University of Queensland Centre for Clinical Research, Herston, Queensland, Australia
  1. Correspondence to Prof Emma L Duncan, Department of Endocrinology, James Mayne Building, Royal Brisbane and Women's Hospital, Butterfield Road, Herston QLD 4029, Australia; e.duncan{at}uq.edu.au

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.

  • acromelic dysplasia
  • acromicric dysplasia
  • geleophysic dysplasia
  • latent transforming factor-beta binding proteins (LTBP)
  • fibrillins

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