Transcriptome Profiling of Primary Skin Fibroblasts Reveal Distinct Molecular Features Between PLOD1- and FKBP14-Kyphoscoliotic Ehlers-Danlos Syndrome.

Lim Lim,Hausser Hausser,Lindert Lindert,Giunta Giunta,Rohrbach Rohrbach,Opitz Opitz

doi:10.3390/genes10070517

Abstract

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 PLOD1 or FKBP14. PLOD1 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. FKBP14 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 PLOD1 or FKBP14 are clinically indistinguishable. We aim to better understand the pathomechanism of kEDS to characterize distinguishing and overlapping molecular features underlying PLOD1-kEDS and FKBP14-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 PLOD1-kEDS and FKBP14-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 PLOD1-kEDS and FKBP14-kEDS, and serves as a tool to better understand the disease.

Highlights

According to the 2017 revised Nosology of the Ehlers–Danlos syndrome (EDS) [1], kyphoscolioticEDS groups two rare autosomal recessive disorders which are clinically indistinguishable, but genetically distinct as they are caused by pathologic biallelic variants in either procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 (PLOD1) or FK506-binding protein 14(FKBP14)
Transcriptome profiling by RNA sequencing identified 298 differentially expressed genes (DEGs) in PLOD1-Kyphoscoliotic Ehlers–Danlos Syndrome (kEDS) patient-derived fibroblasts compared to controls, of which 139 genes were up-regulated and 159 genes were down-regulated in the patients’ cells, as represented in a volcano plot
S3). 488 DEGs were identified in FKBP14-kEDS patient-derived fibroblasts compared to controls, of which 309 genes were up-regulated and 179 genes were down-regulated (Figure 1B, Tables S4 and S5)

Summary

Introduction

According to the 2017 revised Nosology of the Ehlers–Danlos syndrome (EDS) [1], kyphoscolioticEDS (kEDS, OMIM 225400 and 614557) groups two rare autosomal recessive disorders which are clinically indistinguishable, but genetically distinct as they are caused by pathologic biallelic variants in either procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 (PLOD1) or FK506-binding protein 14(FKBP14). EDS (kEDS, OMIM 225400 and 614557) groups two rare autosomal recessive disorders which are clinically indistinguishable, but genetically distinct as they are caused by pathologic biallelic variants in either procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 (PLOD1) or FK506-binding protein 14. PLOD1 encodes the lysyl hydroxylase 1 (LH1) enzyme, which hydroxylates lysyl residues of Xaa-Lys-Gly tripeptide motif in collagens. The lack or loss of function of LH1 leads to underhydroxylation and underglycosylation of lysyl residues in the helical domain of collagen, thereby impairing collagen cross-linking and consequentially causing mechanical instability of the affected connective tissues. Patients deficient in LH1 have an increased ratio of urinary lysyl-pyridinoline to hydroxylysyl-pyridinoline (LP/HP) due to underhydroxylation of collagen lysyl residues. Pathogenic variants in FKBP14 have been described in a group of patients with a clinical diagnosis of kEDS but a normal LP/HP ratio [3,4].

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