A transcriptome study of progeroid neurocutaneous syndrome reveals postn as a new element in proline metabolic disorder

Yu Wen Huang, Ming Fu Chiang, Che Sheng Ho, Pi Lien Hung, Mei Hsin Hsu, Tsung Han Lee, Lichieh Julie Chu, Hsuan Liu, Petrus Tang, Wailap Victor Ng*, Dar Shong Lin

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Aging is a complex biological process. A study of pyrroline-5-carboxylate reductase 1 (PYCR1) deficiency, which causes a progeroid syndrome, may not only shed light on its genetic contribution to autosomal recessive cutis laxa (ARCL) but also help elucidate the functional mechanisms associated with aging. In this study, we used RNA-Seq technology to examine gene expression changes in primary skin fibroblasts from healthy controls and patients with PYCR1 mutations. Approximately 22 and 32 candidate genes were found to be up- and downregulated, respectively, in fibroblasts from patients. Among the downregulated candidates in fibroblasts with PYCR1 mutations, a strong reduction in the expression of 17 genes (53.1%) which protein products are localized in the extracellular space was detected. These proteins included several important ECM components, periostin (POSTN), elastin (ELN), and decorin (DCN); genetic mutations in these proteins are associated with different phenotypes of aging, such as cutis laxa and joint and dermal manifestations. The differential expression of ten selected extracellular space genes was further validated using quantitative RT-PCR. Ingenuity Pathway Analysis revealed that some of the affected genes may be associated with cardiovascular system development and function, dermatological diseases and conditions, and cardiovascular disease. POSTN, one of the most downregulated gene candidates in affected individuals, is a matricellular protein with pivotal functions in heart valvulogenesis, skin wound healing, and brain development. Perturbation of PYCR1 expression revealed that it is positively correlated with the POSTN levels. Taken together, POSTN might be one of the key molecules that deserves further investigation for its role in this progeroid neurocutaneous syndrome.

Original languageEnglish
Pages (from-to)1043-1057
Number of pages15
JournalAging and Disease
Volume9
Issue number6
DOIs
StatePublished - 2018

Keywords

  • Aging
  • ARCL2B
  • Cutis laxa
  • Periostin
  • Progeroid
  • PYCR1

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