Dataset Information

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

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.

SUBMITTER: Lim PJ

PROVIDER: S-EPMC6678841 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Lim Pei Jin PJ Lindert Uschi U Opitz Lennart L Hausser Ingrid I Rohrbach Marianne M Giunta Cecilia C

Genes 20190708 7

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 fi ...[more]

PMID: 31288483

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Project description:Classical Ehlers-Danlos syndrome (cEDS) is a dominant inherited connective tissue disorder mainly caused by mutations in the COL5A1 and COL5A2 genes encoding type V collagen (COLLV), which is a fibrillar COLL widely distributed in a variety of connective tissues. cEDS patients suffer from skin hyperextensibility, abnormal wound healing/atrophic scars, and joint hypermobility. Most of the causative variants result in a non-functional COL5A1 allele and COLLV haploinsufficiency, whilst COL5A2 mutations affect its structural integrity. To shed light into disease mechanisms involved in cEDS, we performed gene expression profiling in skin fibroblasts from four patients harboring haploinsufficient and structural mutations in both disease genes. Transcriptome profiling revealed significant changes in the expression levels of different extracellular matrix (ECM)-related genes, such as SPP1, POSTN, EDIL3, IGFBP2, and C3, which encode both matricellular and soluble proteins that are mainly involved in cell proliferation and migration, and cutaneous wound healing. These gene expression changes are consistent with our previous protein findings on in vitro fibroblasts from other cEDS patients, which exhibited reduced migration and poor wound repair owing to COLLV disorganization, altered deposition of fibronectin into ECM, and an abnormal integrin pattern. Microarray analysis also indicated the decreased expression of DNAJB7, VIPAS39, CCPG1, ATG10, SVIP, which encode molecular chaperones facilitating protein folding, enzymes regulating post-Golgi COLLs processing, and proteins acting as cargo receptors required for endoplasmic reticulum (ER) proteostasis and implicated in the autophagy process. Patients' cells also showed altered mRNA levels of many cell cycle regulating genes including CCNE2, KIF4A, MKI67, DTL, and DDIAS. Protein studies showed that aberrant COLLV expression causes the disassembly of itself and many structural ECM constituents including COLLI, COLLIII, fibronectin, and fibrillins. Our findings provide the first molecular evidence of significant gene expression changes in cEDS skin fibroblasts highlighting that defective ECM remodeling, ER homeostasis and autophagy might play a role in the pathogenesis of this connective tissue disorder.

Dataset Information

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

Publications

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

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