Mutations in LTBP3 cause acromicric dysplasia and geleophysic dysplasia.

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.

• Authors: Aideen M McInerney-Leo, Carine Le Goff, Paul J Leo, Tony J Kenna, Patricia Keith, Jessica E Harris, Ruth Steer, Christine Bole-Feysot, Patrick Nitschke, Cay Kielty, Matthew A Brown, Andreas Zankl, Emma L Duncan, Valerie Cormier-Daire
• Journal: Journal of medical genetics (J Med Genet) Vol. 53 Issue 7 Pg. 457-64 (07 2016) ISSN: 1468-6244 [Electronic] England
• PMID: 27068007 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: 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/

Chemical References

• Fibrillin-1
• LTBP2 protein, human
• LTBP3 protein, human
• Latent TGF-beta Binding Proteins
• Microfilament Proteins
• Transforming Growth Factor beta

Topics

• Bone Diseases, Developmental (genetics)
• Exome (genetics)
• Exons (genetics)
• Fibrillin-1 (genetics)
• Heterozygote
• Humans
• Latent TGF-beta Binding Proteins (genetics)
• Limb Deformities, Congenital (genetics)
• Microfilament Proteins (genetics)
• Mutation
• Mutation, Missense (genetics)
• Phenotype
• Transforming Growth Factor beta (genetics)
• Weill-Marchesani Syndrome (genetics)