{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ADAMTSL2 is a secreted glycoprotein that plays a critical role in extracellular matrix (ECM) organization and the regulation of transforming growth factor‐β (TGF‑β) signaling. Several studies have demonstrated that ADAMTSL2 interacts directly with key ECM components such as latent TGF‑β–binding protein 1 and fibrillin isoforms (FBN1 and FBN2), thereby modulating microfibril assembly and ensuring proper connective tissue homeostasis (for example."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " Moreover, biochemical and expression analyses have shown that ADAMTSL2 is widely expressed during development – including in skeletal muscle, cartilage, and smooth muscle – and that its expression is induced during myogenesis, hinting at a role in cell differentiation and tissue patterning."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In genetic studies, mutations in ADAMTSL2 have been causally linked to autosomal recessive disorders such as geleophysic dysplasia and Musladin‑Lueke syndrome. These mutations often result in protein misfolding and reduced secretion, which in turn lead to disruptions in the microfibrillar network, aberrant TGF‑β signaling, and clinical manifestations including short stature, joint contractures, and cardiac valve defects."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In addition, emerging evidence from clinical genetic studies implicates ADAMTSL2 variants in a broader spectrum of connective tissue disorders with autosomal dominant features."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Functional investigations further indicate that ADAMTSL2 modulates TGF‑β activity in a tissue‑specific manner. For instance, in cardiac fibroblasts, increased levels of extracellular ADAMTSL2 lead to dampened TGF‑β production and signaling, resulting in reduced myofibroblast differentiation and attenuation of fibrotic phenotypes—a finding that positions ADAMTSL2 as a negative regulator of TGF‑β in the failing heart."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Furthermore, its diagnostic utility is suggested by studies in liver disease, where circulating ADAMTSL2 levels distinguish fibrotic from non‑fibrotic states in non‑alcoholic fatty liver disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings establish that ADAMTSL2 is a pivotal ECM-associated regulator that ensures proper microfibril assembly and TGF‑β signaling. Perturbations in its expression or function disrupt tissue architecture and differentiation, linking defective ADAMTSL2 to a range of acromelic dysplasias and fibrotic pathologies.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Carine Le Goff, Fanny Morice-Picard, Nathalie Dagoneau, et al. 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