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Aging and disease    2018, Vol. 9 Issue (6) : 1043-1057     DOI: 10.14336/AD.2018.0222
Orginal Article |
A Transcriptome Study of Progeroid Neurocutaneous Syndrome Reveals POSTN As a New Element in Proline Metabolic Disorder
Huang Yu-Wen1,2, Chiang Ming-Fu3,4,5, Ho Che-Sheng6, Hung Pi-Lien7, Hsu Mei-Hsin7, Lee Tsung-Han2, Chu Lichieh Julie8, Liu Hsuan8,9, Tang Petrus10, Victor Ng Wailap1,11,12,*, Lin Dar-Shong2,6,13,*
1Institute of Biotechnology in Medicine and Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming University, Taipei, Taiwan.
2Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan.
3Department of Neurosurgery, Mackay Memorial Hospital, Taipei, Taiwan.
4Mackay Junior College of Medicine, Nursing and Management, Taipei, Taiwan.
5Graduate Institute of Injury Prevention and Control, Taipei Medical University, Taipei, Taiwan.
6Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan.
7Department of Pediatric Neurology, Kaohsiung Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
8Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan.
9Department of Cell and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
10Molecular Regulation and Bioinformatics Laboratory and Department of Parasitology, Chang Gung University, Taoyuan, Taiwan.
11Institute of Biomedical Informatics and Center for Systems and Synthetic Biology, National Yang Ming University, Taipei, Taiwan.
12Department of Biochemistry, Kaohsiung Medical University, Kaohsiung, Taiwan.
13Department of Medicine, Mackay Medical College, New Taipei, Taiwan
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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.

Keywords Aging      cutis laxa      progeroid      PYCR1      periostin      ARCL2B     
Corresponding Authors: Victor Ng Wailap,Lin Dar-Shong   
About author:

Jiahui Xu and Kun Jiao contributed equally to this work.

Issue Date: 27 November 2017
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Huang Yu-Wen
Chiang Ming-Fu
Ho Che-Sheng
Hung Pi-Lien
Hsu Mei-Hsin
Lee Tsung-Han
Chu Lichieh Julie
Liu Hsuan
Tang Petrus
Victor Ng Wailap
Lin Dar-Shong
Cite this article:   
Huang Yu-Wen,Chiang Ming-Fu,Ho Che-Sheng, et al. A Transcriptome Study of Progeroid Neurocutaneous Syndrome Reveals POSTN As a New Element in Proline Metabolic Disorder[J]. Aging and disease, 2018, 9(6): 1043-1057.
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Figure 1.  Intracellular proline levels of ARCL2B patient primary skin fibroblasts are lower than healthy controls. (A) Overview of proline biosynthesis. Proline is synthesized via glutamate and ornithine routes. The enzymes P5CS and OAT catalyze the conversion of glutamate and ornithine, respectively, to P5C which is subsequently converted to proline by PYCR1 and PYCR2. (B) Intracellular proline levels in the fibroblasts from healthy controls and patients with PYCR1 mutations (n=4). P5C: Δ1-pyrroline-5-carboxylate; GLS: Glutaminase; GAD: Glutamate decarboxylase; GABA: γ- aminobutyric acid; P5CS: P5C synthase; P5CDH: P5C dehydrogenase; OAT: Ornithine aminotransferase; POX: Proline oxidase; PEPD: Proline dipeptidase; ***: p < 0.001
Patient IDP1P2P3P4

PYCR1 mutationsStatusHeterozygousHomozygousHomozygousHeterozygous
Exon4 & 6444 & 5

Clinical featuresLax wrinkled skin++++
Typical facial gestalt++++
Aortic root dilatation
Sinus of Valsalva (mm) (Range) Z-Score
+ +
23.6 (13.56-20.81) 3.47
19.8 (14.16-21.71) 0.97
19.1 (16.59-25.55) -0.86
22.5 (14.05-21.54) 2.46
Cardiovascular systemIRBBBMR, PRTR, MR, RAATR, AR
Joint hyperlaxity++++
Adducted thumb++++
Hip dislocation++++
Shoulder dislocation­++-
Abnormal brain MRI­­­­
Mental retardation++++++/-
Athetoid movements+++­­

Clinical features (neonatal)Thin, translucent skin++++
Postnatal growth delay+++-
Late fontanel closure++++
Blue sclera++++
Table 1  Clinical features manifested in four ARCL2B patients with PYCR1 mutations.
Gene SymbolGene DescriptionFold Change
(Patients/ Controls)a
Subcellular LocationFunctional Type
Genes downregulated in patients
POSTNPeriostin-17.22Extracellular spaceOther
MMP1Matrix metallopeptidase 1-12.22Extracellular spacePeptidase
PTGS2Prostaglandin-endoperoxide synthase 2-9.64CytoplasmEnzyme
EFEMP1EGF containing fibulin like extracellular matrix protein 1-8.69Extracellular spaceEnzyme
IGFBP3Insulin like growth factor binding protein 3-4.44Extracellular spaceOther
JAG1Jagged 1-4.37Extracellular spaceGrowth factor
MYO1DMyosin ID-4.27CytoplasmEnzyme
ELNElastin-3.76Extracellular spaceOther
C1SComplement C1s-3.61Extracellular spacePeptidase
DCNDecorin-3.45Extracellular spaceOther
CYP1B1Cytochrome p450 family 1 subfamily B member 1-3.43CytoplasmEnzyme
PTX3Pentraxin 3-3.35Extracellular spaceOther
STK32BSerine/threonine kinase 32B-3.26OtherKinase
C1RComplement C1r-3.11Extracellular spacePeptidase
FBLN2Fibulin 2-3.06Extracellular spaceOther
ADAM12ADAM metallopeptidase domain 12-2.96Plasma membranePeptidase
SPOCK1SPARC/osteonectin, cwcv and kazal like domains proteoglycan 1-2.95Extracellular spaceOther
CEBPDCCAAT/enhancer binding protein delta-2.85NucleusTranscription regulator
COL3A1Collagen type III alpha 1 chain-2.54Extracellular spaceOther
ADAMTS5ADAM metallopeptidase with thrombospondin type 1 motif 5-2.51Extracellular spacePeptidase
LGR4Leucine rich repeat containing G protein-coupled receptor 4-2.44Plasma membraneTransmembrane receptor
ARL4CADP ribosylation factor like GTPase 4C-2.43NucleusEnzyme
ACKR4Atypical chemokine receptor 4-2.38Plasma membraneG-protein coupled receptor
EMILIN2Elastin microfibril interfacer 2-2.30Extracellular spaceOther
JUNBJUNB proto-oncogene, AP-1 transcription factor subunit-2.28NucleusTranscription regulator
NREPNeuronal regeneration related protein-2.25CytoplasmOther
NNMTNicotinamide N-methyltransferase-2.14CytoplasmEnzyme
ALPK2Alpha kinase 2-2.13NucleusKinase
LMCD1LIM and cysteine rich domains 1-2.09CytoplasmTranscription regulator
NPR3Natriuretic peptide receptor 3-2.07Plasma membraneG-protein coupled receptor
VEGFAVascular endothelial growth factor A-2.05Extracellular spaceGrowth factor
THBS2Thrombospondin 2-2.03Extracellular spaceOther

Genes upregulated in patients
HOXB7Homeobox B723.53NucleusTranscription regulator
STMN2Stathmin 210.52Plasma membraneOther
TRHDEThyrotropin releasing hormone degrading enzyme7.12Plasma membranePeptidase
SPP1Secreted phosphoprotein 13.66Extracellular spaceCytokine
EPDR1Ependymin related 13.54NucleusOther
LBHLimb bud and heart development3.04NucleusTranscription regulator
QPRTQuinolinate phosphoribosyltransferase2.92CytoplasmEnzyme
CRIP2Cysteine rich protein 22.79NucleusOther
CRIP1Cysteine rich protein 12.68CytoplasmOther
MEIS1Meis homeobox 12.58NucleusTranscription regulator
PRLRProlactin receptor2.46Plasma membraneTransmembrane receptor
CBR3Carbonyl reductase 32.37CytoplasmEnzyme
PMAIP1Phorbol-12-myristate-13-acetate-induced protein 12.33CytoplasmOther
PTNPleiotrophin2.28Extracellular spaceGrowth factor
ATF5Activating transcription factor 52.20NucleusTranscription regulator
CSPG4Chondroitin sulfate proteoglycan 42.20Plasma membraneOther
SH2D5SH2 domain containing 52.19Plasma membraneOther
AMIGO2Adhesion molecule with Ig like domain 22.18Plasma membraneOther
CNIH3Cornichon family ampa receptor auxiliary protein 32.17Plasma membraneTransporter
HIST1H4HHistone cluster 1 H4 family member h2.15NucleusOther
ANKRD30BLAnkyrin repeat domain 30B like2.11OtherOther
ADGRE5Adhesion g protein-coupled receptor E52.08Plasma membraneG-protein coupled receptor
Table 2  List of 54 differentially expressed gene candidates in ARCL2B patients’ primary skin fibroblasts.
Figure 2.  PYCR1 mutations affected its mRNA and protein levels in patients’ primary skin fibroblasts. (A) Immunoblot showing the truncated PYCR1 protein p.P115fsX7 is undetectable in fibroblasts from patients (P2 and P3) with homozygous c.345delC mutation, whereas the mutant proteins p.G248E (P1) and p.A187T (P4) are detected in samples with heterozygous mutations. (B) PYCR1 levels relative to GAPDH in four each of healthy control and patients were determined by SYBR Green based qRT-PCR. Data is expressed as mean ± SD from three independent experiments. ** p < 0.01, *** p < 0.001, and **** p < 0.0001. (C) Different single amino acid substitutions in P1 and P4 impeded the PYCR1 half-life as determined by cycloheximide (CHX) chase assay. Cells were harvested and lysed at 0, 4, 8, 16, and 24 h after treatment in medium containing 20 µg/ml CHX. (D) Results in (C) were quantified using the IMAGE J software. α-tubulin was used to normalize the PYCR1 protein levels. The relative levels at 0 hr were defined as 1 for each sample.
Figure 3.  qRT-PCR validated the expression changes of PYCR1 affected extracellular space protein genes. (A) Relative change of the most up- and downregulated expressed genes as determined by RNA-Seq analysis. (B) qRT-PCR validation of the two candidates in (A). (C) Gene ontology (GO) analysis shows enrichment of genes related to extracellular marix/region components are downregulated in patients’ fibroblasts. (D) The expression levels of ten extracellular space protein genes (fold-change > 2, TPM > 10) in the skin fibroblasts of all four patients and three different healthy donors were quantified by qRT-PCR. Data is expressed as mean ± SD from three independent experiments. * p < 0.05, ** p < 0.01.
Figure 4.  IPA analysis indicated differentially expressed gene candidates are associated with cardiovascular, ophthalmic, and dermatological diseases. Genes with fold change > 2 and TPM > 10 were analyzed. (A) Genes implicated in the principal biological function categories related to the catalogues “Diseases and Disorders” and “Physiological System Development and Function”. (B) List of the genes implicated in top five catalogues. The input putatively up- and downregulated genes are indicated by red and green texts, respectively. The molecules located in extracellular space are bold and underlined.
Figure 5.  Perturbations of PYCR1 expression modulate the expression of extracellular space genes in skin fibroblast. (A) Western blot (left) and quantification (right) of PYCR1 and POSTN protein levels in primary skin fibroblasts from controls and patients. Data was expressed as means ± SD from four biological replicates. (B) Evaluation of knockdown efficiencies of pLKO.1 lentiviruses expressing five independent PYCR1 shRNAs in primary skin fibroblasts. At 48 h post-transduction, skin fibroblasts were collected for RNA isolation and qRT-PCR. (C) At 72 h post-transduction, proteins were isolated from fibroblasts and analyzed by Western blot. Scramble shRNA was used as negative control. (D) Knockdown of PYCR1 (shPYCR1 #3, 2MOI) in skin fibroblast modulates the expression of extracellular space genes. (E) Evaluation of the overexpression of PYCR1 in human fibroblasts infected with 2, 5, and 30 MOI of recombinant PYCR1 lentiviruses relative to the empty vector control. (F) Western blot analyses revealed that PYCR1 overexpression (30 MOI) induce POSTN expression in skin fibroblast cells. (G) PYCR1 overexpression in patient’s skin fibroblasts (P2) modulates expression of extracellular space genes. Data was expressed as means ± SD from three biological replicates. NS: not significant, * p < 0.05, ** p < 0.01, *** p < 0.001, and **** p < 0.0001.
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