| Summary: | Kyphoscoliotic Ehlers−Danlos Syndrome (kEDS) is a rare genetic heterogeneous disease clinically characterized by congenital muscle hypotonia, kyphoscoliosis, and joint hypermobility. kEDS is caused by biallelic pathogenic variants in either <i>PLOD1</i> or <i>FKBP14</i>. <i>PLOD1</i> encodes the lysyl hydroxylase 1 enzyme responsible for hydroxylating lysyl residues in the collagen helix, which undergo glycosylation and form crosslinks in the extracellular matrix thus contributing to collagen fibril strength. <i>FKBP14</i> encodes a peptidyl-prolyl cis−trans isomerase that catalyzes collagen folding and acts as a chaperone for types III, VI, and X collagen. Despite genetic heterogeneity, affected patients with mutations in either <i>PLOD1</i> or <i>FKBP14</i> are clinically indistinguishable. We aim to better understand the pathomechanism of kEDS to characterize distinguishing and overlapping molecular features underlying <i>PLOD1</i>-kEDS and <i>FKBP14</i>-kEDS, 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 <i>PLOD1</i>-kEDS and <i>FKBP14</i>-kEDS. Furthermore, we identified genes involved in inner ear development, vascular remodeling, endoplasmic reticulum (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 <i>PLOD1</i>-kEDS and <i>FKBP14</i>-kEDS, and serves as a tool to better understand the disease.
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