Transcriptome profiling of primary skin fibroblasts reveal distinct molecular features between PLOD1- and FKBP14-kyphoscoliotic Ehlers-Danlos Syndrome

Kyphoscoliotic Ehlers-Danlos Syndrome (kEDS) is a rare heritable disease characterised by congenital muscle hypotonia, kyphoscoliosis and joint hypermobility. Pathogenic variants of kEDS include mutations in PLOD1 or FKBP14 genes. PLOD1 encodes lysyl hydroxylase 1 enzyme which hydroxylates lysine residues in the collagen helix, allowing glycosylation and crosslinking that contribute to fibril strength, while FKBP14 encodes a peptidyl-prolyl cis-trans isomerase that catalyses collagen folding and acts as a chaperone for types III, VI and X collagen. We aim to better characterise the pathology of kEDS in order to distinguish the molecular features underlying PLOD1-kEDS and FKBP14-kEDS despite overlapping phenotypes to facilitate diagnosis, and to identify novel molecular targets that may expand treatment strategies. Transcriptome profiling by RNA-sequencing of patient-derived skin fibroblasts revealed differential expression of genes encoding extracellular matrix components that are unique between PLOD1-kEDS and FKBP14-kEDS. Furthermore, we identified genes involved in inner ear development, vascular remodelling, ER stress and protein trafficking that were differentially expressed in patient fibroblasts compared to controls. Overall, our study presents the first transcriptomics data in kEDS revealing distinct molecular features between PLOD1-kEDS and FKBP14-kEDS and serves as a tool to better understand the disease pathology.