Extracellular matrix abnormalities in Hutchinson-Gilford progeria fibroblasts: a specific defect in collagen IV and...

Hutchinson-Gilford progeria (HGPS) is a rare genetic disorder characterized by clinical features that mimic accelerated aging. The classical form of progeria is caused by a heterozygous pathogenic variant in in the LMNA gene resulting in the truncated lamin A protein progerin that accumulates in the nuclear envelope and exerts toxic effects on connective tissue and bone growth. Although connective tissue abnormalities are a hallmark of the disease, the extracellular matrix (ECM) produced by HGPS fibroblasts has not been systematically characterized. Here, we combined analysis of four RNA-seq datasets with functional and secretome analyses of primary dermal fibroblasts from an infant with HGPS. Transcriptomic analyses identified enrichment of basement membrane-related pathways and consistent dysregulation of the matrisome gene COL4A1. Patient fibroblasts recapitulated canonical HGPS phenotypes, including progerin accumulation, altered nuclear morphology, reduced proliferation, early senescence, and changes in cell mechanics. Secretome proteomics revealed selective downregulation of core basement membrane components, including collagen IV chains with corresponding transcriptional reductions and aberrant collagen IV deposition in vitro. In 3D skin equivalents, HGPS fibroblasts failed to support proper dermo-epidermal basement membrane assembly, a defect mirrored by reduced collagen IV staining in patient skin tissue. Together, these findings identify impaired basement membrane composition and organization as a previously underappreciated feature of HGPS and suggest that ECM remodeling may contribute to cutaneous pathology and potentially broader disease manifestations.