From tall to short: The role of TGFβ signaling in growth and its disorders

The acromelic dysplasia group is characterized by short stature, short hands and feet, stiff joint, and muscular build. Four disorders can now be ascribed to this group, namely WeillMarchesani syndrome (WMS), geleophysic dysplasia (GD), acromicric dysplasia (AD), and Myhre syndrome (MS). Although closely similar, they can be distinguished by subtle clinical features and their pattern inheritance. WMS is characterized by the presence of dislocation of microspherophakia and has autosomal dominant or recessive mode of inheritance. GD is the more severe one, with a progressive cardiac valvular thickening, tracheal stenosis, bronchopulmonary insufficiency, often leading to an early death. AD has an autosomal dominant mode of inheritance, distinct facial and skeleton features (a hoarse voice and internal notch of the femoral head). Finally, MS is sporadic, characterized by prognathism, deafness, developmental delay, thickened calvarium, and large vertebrae with short and large pedicles. We first identified mutations in Fibrillin-1 (FBN1) in the dominant form of WMS and then mutations in A Disintegrin-like And Metalloproteinase domain with ThromboSpondin type 1 repeats 10 (ADAMTS10) in the recessive form of WMS. The function of ADAMTS10 is unknown but these findings support a direct interaction between ADAMTS10 and FBN1. We then identified mutations in ADAMTSL2 in the recessive form of GD and a hotspot of mutations in FBN1 in the dominant form of GD and in AD (exon 4142, encoding TGF beta binding protein-like domain 5 (TB5) of FBN1). The function of ADAMTSL2 is unknown. Using a yeast double hybrid screen, we identified latent transforming growth factor-beta (TGF beta) binding protein 1 as a partner of ADAMTSL2. We found an increased level of active TGF beta in the fibroblast medium from patients with FBN1 or ADAMTSL2 mutations and an enhanced phosphorylated SMAD2 level, allowing us to conclude at an enhanced TGF beta signaling in GD and AD. Finally, a direct interaction between ADAMTSL2 and FBN1 was demonstrated suggesting a dysregulation of FBN1/ADAMTSL2 interrelationship as the underlying mechanism of the short stature phenotypes. Using exome sequencing in MS probands, we identified de novo SMAD4 missense mutations, all involving isoleucine residue at position 500, in the MH2 domain. In MS fibroblasts, we found decreased ubiquitination level of SMAD4 and increased level of SMAD4 supporting a stabilization of SMAD4 protein. Functional SMAD4 is required for canonical signal transduction through the oligomerization with phosphorylated SMAD2/3 and SMAD1/5/8. We therefore studied the nuclear localization of mutant SMAD complexes and found that the complexes translocate to the nucleus. We finally observed a decreased expression of downstream TGF beta target genes supporting impaired TGF beta driven transcriptional control in MS. Our findings support a direct link between the short stature phenotypes and the TGF beta signaling. However, the finding of enhanced TGF beta signaling in Marfan phenotypes supports the existence of yet unknown mechanisms regulating TGF beta action. (C) 2012 Wiley Periodicals, Inc.