Acromelic dysplasias: how rare musculoskeletal disorders reveal biological functions of extracellular matrix proteins

Acromelic dysplasias are a group of rare musculoskeletal disorders that collectively present with short stature, pseudomuscular build, stiff joints, and tight skin. Acromelic dysplasias are caused by mutations in genes (FBN1,ADAMTSL2,ADAMTS10,ADAMTS17,LTBP2, andLTBP3) that encode secreted extracellular matrix proteins, and inSMAD4, an intracellular coregulator of transforming growth factor-beta (TGF-beta) signaling. The shared musculoskeletal presentations in acromelic dysplasias suggest that these proteins cooperate in a biological pathway, but also fulfill distinct roles in specific tissues that are affected in individual disorders of the acromelic dysplasia group. In addition, most of the affected proteins directly interact with fibrillin microfibrils in the extracellular matrix and have been linked to the regulation of TGF-beta signaling. Together with recently developed knockout mouse models targeting the affected genes, novel insights into molecular mechanisms of how these proteins regulate musculoskeletal development and homeostasis have emerged. Here, we summarize the current knowledge highlighting pathogenic mechanisms of the different disorders that compose acromelic dysplasias and provide an overview of the emerging biological roles of the individual proteins that are compromised. Finally, we develop a conceptual model of how these proteins may interact and form an acromelic dysplasia complex on fibrillin microfibrils in connective tissues of the musculoskeletal system.

Automated summary

Acromelic dysplasias are rare musculoskeletal disorders caused by mutations in genes encoding proteins that cooperate in a biological pathway but have distinct roles in specific tissues. Most affected proteins interact with fibrillin microfibrils and regulate TGF-beta signaling, contributing to musculoskeletal development and homeostasis.