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Acromelic dysplasias are caused by mutations in genes (<jats:italic>FBN1<\/jats:italic>, <jats:italic>ADAMTSL2<\/jats:italic>, <jats:italic>ADAMTS10<\/jats:italic>, <jats:italic>ADAMTS17<\/jats:italic>, <jats:italic>LTBP2<\/jats:italic>, and <jats:italic>LTBP3<\/jats:italic>) that encode secreted extracellular matrix proteins, and in <jats:italic>SMAD4<\/jats:italic>, an intracellular coregulator of transforming growth factor\u2010\u03b2 (TGF\u2010\u03b2) 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\u2010\u03b2 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 \u201cacromelic dysplasia complex\u201d on fibrillin microfibrils in connective tissues of the musculoskeletal system.<\/jats:p>","DOI":"10.1111\/nyas.14465","type":"journal-article","created":{"date-parts":[[2020,9,3]],"date-time":"2020-09-03T05:39:26Z","timestamp":1599111566000},"page":"57-76","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Acromelic dysplasias: how rare musculoskeletal disorders reveal biological functions of extracellular matrix proteins"],"prefix":"10.1111","volume":"1490","author":[{"given":"Sarah","family":"Stanley","sequence":"first","affiliation":[{"name":"Leni &amp; Peter W. May Department of Orthopedics Icahn School of Medicine at Mount Sinai  New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zerina","family":"Balic","sequence":"additional","affiliation":[{"name":"Leni &amp; Peter W. May Department of Orthopedics Icahn School of Medicine at Mount Sinai  New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1569-9451","authenticated-orcid":false,"given":"Dirk","family":"Hubmacher","sequence":"additional","affiliation":[{"name":"Leni &amp; Peter W. 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