A Transcriptome Study of Progeroid Neurocutaneous Syndrome Reveals POSTN As a New Element in Proline Metabolic Disorder.

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

doi:10.14336/ad.2018.0222

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.

Highlights

We provided the first characterization of the transcriptome for pyrroline-5-carboxylate reductase 1 (PYCR1) mutations causing the neurocutaneous syndrome ARCL2B
This study revealed previously unknown associations between the PYCR1 mutation and molecular changes in patients with ARCL2B
No effective therapeutic strategies are yet available for ARCL2B, and the underlying mechanisms involved in disease-related changes require further elucidation

Summary

Introduction

A study of pyrroline-5-carboxylate reductase 1 (PYCR1) deficiency, which causes a progeroid syndrome, may shed light on its genetic contribution to autosomal recessive cutis laxa (ARCL) and help elucidate the functional mechanisms associated with aging. 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. Autosomal recessive cutis laxa (ARCL) includes several connective tissue disorder syndromes characterized by abnormal elastic fibers, resulting in sagging, inelastic, and wrinkled skin It involves multiple organ systems, leading to multisystem disorder characterized by premature aging. This work helps elucidate the functional mechanisms associated with aging and provides the first characterization of the transcriptomic basis for PYCR1 mutations causing autosomal recessive neurocutaneous syndrome

Methods

Results

Conclusion