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

  • Lim PJ Connective Tissue Unit, Division of Metabolism and Children's Research Centre, University Children's Hospital, 8032 Zürich, Switzerland.
  • Lindert U Connective Tissue Unit, Division of Metabolism and Children's Research Centre, University Children's Hospital, 8032 Zürich, Switzerland.
  • Opitz L Functional Genomics Center Zurich, University of Zurich/ETH Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
  • Hausser I Institute of Pathology, Heidelberg University Hospital, 69120 Heidelberg, Germany.
  • Rohrbach M Connective Tissue Unit, Division of Metabolism and Children's Research Centre, University Children's Hospital, 8032 Zürich, Switzerland. Marianne.Rohrbach@kispi.uzh.ch.
  • Giunta C Connective Tissue Unit, Division of Metabolism and Children's Research Centre, University Children's Hospital, 8032 Zürich, Switzerland. Cecilia.Giunta@kispi.uzh.ch.
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  • 2019-07-11
Published in:
  • Genes. - 2019
EDS type VI
FKBP14
PLOD1
connective tissue
extracellular matrix
kyphoscoliotic Ehlers–Danlos Syndrome
transcriptomics
Adolescent
Adult
Cells, Cultured
Child
Child, Preschool
Ehlers-Danlos Syndrome
Female
Fibroblasts
Gene Expression Profiling
Humans
Male
Middle Aged
Peptidylprolyl Isomerase
Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase
Skin
English 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.
Language
  • English
Open access status
gold
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https://sonar.ch/global/documents/185200
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