An Adamts2 Knock-In Model of Dermatosparaxis Ehlers–Danlos Syndrome Reveals Defective Collagen Maturation

Abstract

Background/Objectives: Dermatosparaxis Ehlers–Danlos syndrome (dEDS) is a rare autosomal recessive connective tissue disorder caused by biallelic pathogenic variants in ADAMTS2, which encodes the primary N-proteinase responsible for fibrillar procollagen processing. Although defective procollagen cleavage is the defining molecular feature of dEDS, how ADAMTS2 deficiency disrupts extracellular matrix (ECM) organization and tissue integrity remains incompletely understood. Here we characterized the structural, molecular, and cellular consequences of a knock-in Adamts2 mouse model harboring a disease-associated variant and assessed its phenotypic and mechanistic resemblance to human dEDS. Methods: We generated Adamts2Q226* mice carrying a variant analogous to a human dEDS-causing mutation. Skin from homozygous, heterozygous, and control animals was evaluated using histologic, ultrastructural, biochemical, digital pathology, and single-nucleus RNA-sequencing approaches. Pathway enrichment analyses and the computational tool CellChat were used to infer altered molecular programs and changes in intercellular communication. Results: Homozygous knock-in mice exhibited near-complete loss of dermal ADAMTS2 protein expression, impaired type I procollagen processing, disrupted dermal architecture, and irregular hieroglyphic collagen fibrils characteristic of dEDS. Digital pathology demonstrated reduced collagen bulk, diminished assembled and total collagen, increased fine collagen, and loss of mature collagen architecture, with intermediate changes in heterozygous animals. Single-nucleus RNA sequencing identified fibroblasts as the most affected population, with coordinated downregulation of collagen, microfibrillar, and other ECM-associated genes. Pathway analyses implicated altered ECM organization, receptor-linked signaling, cytoskeletal regulation, protein processing, and metabolism, while CellChat inferred widespread reductions in intercellular communication. Conclusions: ADAMTS2 deficiency causes fibroblast-enriched transcriptional remodeling, impaired collagen processing and ECM maturation, and disrupted tissue-wide cellular communication. This model provides a translational platform for studying dEDS pathogenesis and strategies to restore ECM homeostasis.