Mutations in LTBP3 cause acromicric dysplasia and geleophysic dysplasia

作者：McInerney Leo Aideen M; Le Goff Carine; 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

来源：Journal of Medical Genetics, 2016, 53(7): 457-464.

DOI：10.1136/jmedgenet-2015-103647

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 beta (TGF-beta)-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 beta (TGF-beta)-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(star)Cysext(star)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.

• 出版日期2016-7