ABSTRACT: Dermatosparaxis Ehlers–Danlos syndrome (dEDS) is a rare autosomal recessive connective tissue disorder caused by biallelic pathogenic variants in ADAMTS2, which encodes the principal N-proteinase responsible for processing fibrillar procollagens. Although defective procollagen cleavage is a defining feature of dEDS, the downstream cellular and tissue-level mechanisms linking ADAMTS2 deficiency to extracellular matrix (ECM) failure remain incompletely understood. To investigate this, we generated a patient-analog Adamts2Q226*/Q226* knock-in mouse model and used histologic, ultrastructural, biochemical, digital pathology, and single-nucleus transcriptomic approaches to define the consequences of ADAMTS2 loss in skin. Homozygous mutant mice exhibited near-complete loss of dermal Adamts2 expression, impaired type I procollagen processing, disrupted dermal architecture, and irregular hieroglyphic collagen fibrils characteristic of dEDS. Quantitative digital pathology further demonstrated reduced collagen bulk, diminished assembled and total collagen, increased fine collagen, and broad loss of mature collagen architecture in homozygous skin, with more limited intermediate changes in heterozygous animals. Single-nucleus RNA sequencing identified fibroblasts as the cell population most strongly affected by Adamts2 deficiency, with coordinated downregulation of collagen, microfibrillar, and other ECM-associated genes. Pathway analyses further implicated altered ECM organization, receptor-linked signaling, cytoskeletal regulation, protein processing, and metabolic programs, while CellChat analysis revealed a widespread reduction in inferred intercellular communication across the skin microenvironment. Collectively, these findings establish a genetically faithful knock-in model of dEDS and demonstrate that ADAMTS2 deficiency causes fibroblast-centered transcriptional remodeling, impaired ECM maturation, and disruption of tissue-wide cellular communication. This model provides a translational platform for defining dEDS pathogenesis and testing strategies aimed at restoring collagen processing and ECM homeostasis.
