Mutations in LTBP3 cause acromicric dysplasia and geleophysic dysplasia

McInerney-Leo, Aideen M., Goff, Carine Le, Leo, Paul J., Kenna, Tony J., Keith, Patricia, Harris, Jessica E., Steer, Ruth, Bole-Feysot, Christine, Nitschke, Patrick, Kielty, Cay, Brown, Matthew A., Zankl, Andreas, Duncan, Emma L. and Cormier-Daire, Valerie (2016) Mutations in LTBP3 cause acromicric dysplasia and geleophysic dysplasia. Journal of Medical Genetics, 53 7: 457-464. doi:10.1136/jmedgenet-2015-103647

Author McInerney-Leo, Aideen M.
Goff, Carine Le
Leo, Paul J.
Kenna, Tony J.
Keith, Patricia
Harris, Jessica E.
Steer, Ruth
Bole-Feysot, Christine
Nitschke, Patrick
Kielty, Cay
Brown, Matthew A.
Zankl, Andreas
Duncan, Emma L.
Cormier-Daire, Valerie
Title Mutations in LTBP3 cause acromicric dysplasia and geleophysic dysplasia
Formatted title
Mutations in LTBP3 cause acromicric dysplasia and geleophysic dysplasia
Journal name Journal of Medical Genetics   Check publisher's open access policy
ISSN 1468-6244
Publication date 2016-04-11
Year available 2016
Sub-type Article (original research)
DOI 10.1136/jmedgenet-2015-103647
Open Access Status Not Open Access
Volume 53
Issue 7
Start page 457
End page 464
Total pages 9
Place of publication London, United Kingdom
Publisher B M J Group
Collection year 2017
Language eng
Formatted 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 ß (TGF-ß)-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 ß (TGF-ß)-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.
Keyword Latent transforming growth factor β (TGF-β)-binding protein-3
Acromicric dysplasia
Geleophysic dysplasia
Microfibrillar network
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
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UQ Diamantina Institute Publications
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