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Supplementary material J Med Genet Table S1. List of 263 genes included in the AGS-LEUK panel. Axonal Guidance Signaling genes as AGS and Leukocyte transvasation genes as LEUK. List of genes (AGS) List of genes (LEUK) ABLIM1 CLDN11 ACTR3 MMP14 ADAM11 MMP15 ADAM23 CTNNA1 ADAMTS1 ENSG00000130396 ADAMTS4 CLDN6 ADAMTS9 MMP24 ARHGEF15 ARHGAP12 ARHGEF6 DLC1 ARPC1B TIMP2 BDNF RAPGEF3 BMP1 F11R BMP4 CLDN23 BMP6 CLDN8 BMP7 JAM3 CXCL12 CLDN3 CXCR4 ARHGAP8 DPYSL5 ICAM1 EFNA1 MMP16 EFNA5 JAM2 ENPEP CLDN7 EPHA1 TIMP3 EPHA3 VCAM1 EPHA5 CLDN5 EPHA7 MSN EPHB1 NOX3 EPHB2 ACTC1 EPHB4 VAV2 FGFR2 CLDN10 FZD1 RAP1GAP FZD10 VAV3 FZD5 MAPK10 FZD6 CTNNA2 GAB1 CDH5 GLI1 PECAM1 GLI3 CTNND1 GNA14 ITGA4 GNAI1 CLDN16 GNAO1 CLDN9 GNAS CLDN15 GNB4 CLDN22 GNG11 OCLN GNG2 ESAM Gallego-Martinez A, et al. J Med Genet 2019; 0:1–7. doi: 10.1136/jmedgenet-2019-106159 Supplementary material J Med Genet GNG7 ACTB IGF1 CYBA IRS1 CTNNB1 IRS2 MMP9 ITGA3 MAPK14 ITGB1 MAPK11 LIMK1 MAPK12 LIMK2 MAPK13 LINGO1 PRKCB LRRC4C PXN MME BCAR1 MMP11 THY1 MMP2 ARHGAP5 MRAS MYL2 MYL9 MYLPF NFATC4 RAP1A NGFR RAP1B NOTUM VASP NRP1 ACTN4 NTN3 ACTN1 NTRK2 VCL NTRK3 RAPGEF4 PAK3 ITK PAK4 VAV1 PAPPA2 PDGFA PDGFC PIK3CB PIK3R1 PLCE1 PLCH1 PLCH2 PLXNA2 PLXNB1 PLXND1 PPP3CA PRKACB PRKAR2A PRKAR2B PRKCA PRKCZ PRKD3 ROBO2 SDC2 SDCBP Gallego-Martinez A, et al. J Med Genet 2019; 0:1–7. doi: 10.1136/jmedgenet-2019-106159 Supplementary material J Med Genet SEMA3B SEMA3C SEMA3E SEMA3F SEMA4F SEMA4G SEMA5A SEMA6B SEMA6D SEMA7A SHC1 SLIT2 SLIT3 STK36 TUBA4A TUBB2B TUBB4A TUBB4B TUBB6 UNC5C UNC5D ENSG00000165197 WIPF1 WNT3 WNT5A WNT7A WNT7B NTNG1 NTNG2 LRRC4 NTN4 TRPC1 TRPC3 TRPC6 PPP3CB PPP3CC PPP3R1 NFATC2 NFATC3 PTK2 FYN RAC1 CDC42 ABLIM2 NCK1 PAK1 PAK2 Gallego-Martinez A, et al. J Med Genet 2019; 0:1–7. doi: 10.1136/jmedgenet-2019-106159 Supplementary material J Med Genet PAK6 RHOA ROCK1 ROCK2 PTPN11 EFNB1 EFNB2 EFNB3 EPHA4 ABL1 ENAH RASA1 KRAS NRAS MAPK1 RGS3 GNAI3 GNAI2 ROBO1 SRGAP2 SRGAP1 SRGAP3 SEMA3A PLXNA3 PLXNA4 CFL1 CFL2 RHOD DPYSL2 CDK5 GSK3B SEMA4D SEMA4B SEMA4C SEMA5B SEMA6A PLXNB2 RAF1 RRAS PLXNC1 PTCH1 SMO ILK BOC WNT5B FZD3 RYK Gallego-Martinez A, et al. J Med Genet 2019; 0:1–7. doi: 10.1136/jmedgenet-2019-106159 Supplementary material J Med Genet CAMK2D CAMK2B CAMK2G WNT4 PIK3CA PIK3R3 PDK1 PARD3 PARD6A PARD6G SSH1 SSH3 BMPR2 BMPR1B Gallego-Martinez A, et al. J Med Genet 2019; 0:1–7. doi: 10.1136/jmedgenet-2019-106159 Supplementary material J Med Genet Table S2. Number of exonic variants found after variant calling and frequency filtering. Exonic total 2194 Missense 1189 Synonymous 966 Stopgain 32 Stoploss 5 Startloss 2 Gallego-Martinez A, et al. J Med Genet 2019; 0:1–7. doi: 10.1136/jmedgenet-2019-106159 Supplementary material J Med Genet Table S3. List of all the genes considered from the missense analysis with OR > 1. Missense CSVS Gene OR(CI) Pvalue PvalueIF SHC1 18.94 (7.75-55.68) 1.54398E-15 0.000334 NOX3 6.96 (3.87-12.91) 4.03682E-12 0.002338 PRKD3 2.03 (1.56-2.63) 8.35583E-08 0.026857 NTN4 7.22 (3.07-18.3) 7.52201E-07 0.04584 DLC1 2.15 (1.55-2.95) 2.76422E-06 0.062827 PTK2 4.74 (2.35-9.77) 4.13399E-06 0.069242 SEMA4F 1.84 (1.41-2.39) 5.53808E-06 0.074303 STK36 1.6 (1.28-1.98) 2.28373E-05 0.104459 BMP1 1.73 (1.34-2.24) 2.70986E-05 0.10883 EPHA5 1.91 (1.37-2.65) 0.00012908 0.157918 AP000349.1 1.98 (1.38-2.82) 0.000182601 0.171454 EPHA7 1.68 (1.28-2.2) 0.000192955 0.173708 NCK1 1.86 (1.33-2.58) 0.000215017 0.178215 ARPC1B 1.96 (1.35-2.81) 0.000320759 0.195868 IRS1 1.55 (1.2-1.98) 0.0005828 0.225397 PIK3CA 1.48 (1.16-1.87) 0.001560294 0.283608 PLXNA4 1.94 (1.27-2.92) 0.00162882 0.286448 RGS3 1.44 (1.14-1.81) 0.001948863 0.298597 PLCE1 1.55 (1.17-2.05) 0.00222802 0.307976 VCL 3.14 (1.41-6.89) 0.002846545 0.32586 SSH3 2 (1.23-3.21) 0.003293191 0.336955 ESAM 7.13 (1.52-44.19) 0.005039489 0.371373 ADAMTS4 1.47 (1.11-1.92) 0.005565848 0.379862 KCNQ3 1.99 (1.18-3.3) 0.00655371 0.394209 MLLT4 1.51 (1.11-2.04) 0.006963292 0.399656 PLXND1 1.76 (1.15-2.66) 0.007679725 0.4086 RHOD 1.8 (1.14-2.8) 0.009323239 0.426844 FZD6 5.94 (1.15-38.28) 0.015650912 0.479168 ROCK1 1.98 (1.1-3.49) 0.016506139 0.484846 DPYSL5 1.43 (1.05-1.94) 0.018133847 0.495025 ARHGAP5 1.83 (1.07-3.08) 0.020144781 0.506622 ARHGAP8 1.89 (1.03-3.35) 0.025288899 0.532482 SUCLG2 1.26 (1.02-1.55) 0.02973562 0.551559 GNA14 2.46 (1.03-5.66) 0.03197755 0.560297 ABL1 1.43 (1-2.02) 0.040398752 0.589145 RAF1 4.75 (0.8-32.46) 0.045892271 0.605354 SLIT2 4.75 (0.8-32.46) 0.045892271 0.605354 PARD6A 1.35 (0.99-1.81) 0.047497626 0.609782 EPHA3 1.27 (1-1.6) 0.04947228 0.615059 BMPR2 1.45 (0.98-2.1) 0.055591766 0.630352 MMP15 1.69 (0.91-3.06) 0.073463879 0.667979 FZD10 1.44 (0.93-2.18) 0.091178171 0.69812 BOC 1.95 (0.87-4.13) 0.09257319 0.700268 PLXNC1 1.36 (0.92-1.96) 0.095647475 0.704904 ACTN1 1.43 (0.93-2.15) 0.096315071 0.705893 FGFR2 2.19 (0.79-5.73) 0.107026958 0.720982 Gallego-Martinez A, et al. J Med Genet 2019; 0:1–7. doi: 10.1136/jmedgenet-2019-106159 Supplementary material J Med Genet SEMA3C 2.37 (0.69-7.49) 0.113796227 0.729834 SEMA5B 1.39 (0.9-2.1) 0.119942558 0.737468 RAPGEF4 3.56 (0.48-26.58) 0.124620138 0.743043 WNT7A 3.56 (0.48-26.58) 0.124620138 0.743043 SEMA3F 3.56 (0.48-26.58) 0.124620138 0.743043 PLCH1 3.56 (0.48-26.58) 0.124620138 0.743043 CLDN11 3.56 (0.48-26.58) 0.124620138 0.743043 LRRC4 3.56 (0.48-26.58) 0.124620138 0.743043 NTRK2 3.56 (0.48-26.58) 0.124620138 0.743043 WNT5B 3.56 (0.48-26.58) 0.124620138 0.743043 TRPC6 1.17 (0.94-1.45) 0.162248864 0.781938 ITGA4 1.98 (0.52-6.59) 0.206503116 0.817935 GLI1 1.98 (0.52-6.59) 0.206503116 0.817935 PIK3R3 2.37 (0.49-10.02) 0.241385079 0.841262 PAPPA2 2.37 (0.49-10.02) 0.241385079 0.841262 LIMK2 2.37 (0.49-10.02) 0.241385079 0.841262 SEMA4G 1.24 (0.81-1.86) 0.286124599 0.866502 ROBO2 2.37 (0.2-20.7) 0.303796962 0.875311 BMPR1B 2.37 (0.2-20.7) 0.303796962 0.875311 UNC5C 2.37 (0.2-20.7) 0.303796962 0.875311 ITK 2.37 (0.2-20.7) 0.303796962 0.875311 MAPK14 2.37 (0.2-20.7) 0.303796962 0.875311 GLI3 2.37 (0.2-20.7) 0.303796962 0.875311 LIMK1 2.37 (0.2-20.7) 0.303796962 0.875311 PTCH1 2.37 (0.2-20.7) 0.303796962 0.875311 LINGO1 2.37 (0.2-20.7) 0.303796962 0.875311 PRKCB 2.37 (0.2-20.7) 0.303796962 0.875311 ARHGEF15 2.37 (0.2-20.7) 0.303796962 0.875311 MMP24 2.37 (0.2-20.7) 0.303796962 0.875311 CTNND1 1.56 (0.54-4.01) 0.3171239 0.881582 SRGAP1 1.4 (0.63-2.91) 0.334653758 0.889384 PARD3 1.32 (0.64-2.58) 0.382814 0.908535 ALDH5A1 1.15 (0.79-1.66) 0.404046407 0.916048 NRP1 1.78 (0.29-8.34) 0.422095294 0.922041 SEMA6B 1.78 (0.29-8.34) 0.422095294 0.922041 PLXNA2 1.16 (0.74-1.78) 0.44653005 0.929624 EPHA1 1.58 (0.35-5.67) 0.499948603 0.944303 PAK4 1.58 (0.35-5.67) 0.499948603 0.944303 VAV3 1.27 (0.55-2.71) 0.554291737 0.956916 ADAM23 1.18 (0.12-6.63) 0.690574025 0.980241 SEMA3E 1.18 (0.12-6.63) 0.690574025 0.980241 FZD3 1.18 (0.12-6.63) 0.690574025 0.980241 MAPK13 1.18 (0.21-4.75) 0.733336354 0.985488 FZD5 1.05 (0.76-1.43) 0.752627915 0.987568 SEMA6D 1.11 (0.32-3.18) 0.794183285 0.991465 EPHB2 1.18 (0.02-14.75) 1 1 F11R 1.18 (0.02-14.75) 1 1 ENAH 1.18 (0.02-14.75) 1 1 PDK1 1.18 (0.02-14.75) 1 1 WIPF1 1.18 (0.02-14.75) 1 1 Gallego-Martinez A, et al. J Med Genet 2019; 0:1–7. doi: 10.1136/jmedgenet-2019-106159 Supplementary material J Med Genet ROBO1 1.18 (0.02-14.75) 1 1 RASA1 1.18 (0.02-14.75) 1 1 UNC5D 1.18 (0.02-14.75) 1 1 SEMA4D 1.18 (0.02-14.75) 1 1 ARHGAP12 1.18 (0.02-14.75) 1 1 MYL2 1.18 (0.02-14.75) 1 1 MMP14 1.18 (0.02-14.75) 1 1 SEMA4B 1.18 (0.02-14.75) 1 1 CLDN6 1.18 (0.02-14.75) 1 1 AFG3L2 1.18 (0.02-14.75) 1 1 ADAMTS1 1.18 (0.02-14.75) 1 1 Gallego-Martinez A, et al.
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  • Orally Administered Glucosylceramide Improves the Skin Barrier Function by Upregulating Genes Associated with the Tight Junction and Cornified Envelope Formation

    Orally Administered Glucosylceramide Improves the Skin Barrier Function by Upregulating Genes Associated with the Tight Junction and Cornified Envelope Formation

    110215 (251) Biosci. Biotechnol. Biochem., 75 (8), 110215-1–8, 2011 Orally Administered Glucosylceramide Improves the Skin Barrier Function by Upregulating Genes Associated with the Tight Junction and Cornified Envelope Formation y Ritsuro IDETA, Tomohiro SAKUTA, Yusuke NAKANO, and Taro UCHIYAMA Shiseido Functional Food Research and Development Center, 2-12-1 Fukuura, Kanazawa-ku, Yokohama 236-8643, Japan Received March 18, 2011; Accepted May 9, 2011; Online Publication, August 7, 2011 [doi:10.1271/bbb.110215] Dietary glucosylceramide improves the skin barrier mammalian skin barrier function through their role as function. We used a microarray system to analyze the intracellular lipids.6) The skin barrier is essential for mRNA expression in SDS-treated dorsal skin of the protecting against physical stimuli, thermal challenge, hairless mouse to elucidate the molecular mechanisms ultraviolet light (UV), chemical substances and micro- involved. The transepidermal water loss of mouse skin organisms, as well as for preventing water loss.7) The was increased by the SDS treatment, this increase being barrier function is mainly localized in the stratum significantly reduced by a prior oral administration of corneum (SC) which is formed in the outermost layer of glucosylceramides. The microarray-evaluated mRNA the epidermis and consists of the cornified envelope expressionAdvance ratio showed a statistically significant View in- (CE) and intercellular multilamellar lipids. CE forms crease in the expression of genes related to the cornified a highly durable and flexible barrier8) comprising a envelope and tight junction formation when compared 15-nm-thick structure composed of such insoluble with all genes in the glucosylceramide-fed/SDS-treated proteins as involucrin, loricrin, and small proline-rich mouse skin.
  • Supplementary Table 1: Adhesion Genes Data Set

    Supplementary Table 1: Adhesion Genes Data Set

    Supplementary Table 1: Adhesion genes data set PROBE Entrez Gene ID Celera Gene ID Gene_Symbol Gene_Name 160832 1 hCG201364.3 A1BG alpha-1-B glycoprotein 223658 1 hCG201364.3 A1BG alpha-1-B glycoprotein 212988 102 hCG40040.3 ADAM10 ADAM metallopeptidase domain 10 133411 4185 hCG28232.2 ADAM11 ADAM metallopeptidase domain 11 110695 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 195222 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 165344 8751 hCG20021.3 ADAM15 ADAM metallopeptidase domain 15 (metargidin) 189065 6868 null ADAM17 ADAM metallopeptidase domain 17 (tumor necrosis factor, alpha, converting enzyme) 108119 8728 hCG15398.4 ADAM19 ADAM metallopeptidase domain 19 (meltrin beta) 117763 8748 hCG20675.3 ADAM20 ADAM metallopeptidase domain 20 126448 8747 hCG1785634.2 ADAM21 ADAM metallopeptidase domain 21 208981 8747 hCG1785634.2|hCG2042897 ADAM21 ADAM metallopeptidase domain 21 180903 53616 hCG17212.4 ADAM22 ADAM metallopeptidase domain 22 177272 8745 hCG1811623.1 ADAM23 ADAM metallopeptidase domain 23 102384 10863 hCG1818505.1 ADAM28 ADAM metallopeptidase domain 28 119968 11086 hCG1786734.2 ADAM29 ADAM metallopeptidase domain 29 205542 11085 hCG1997196.1 ADAM30 ADAM metallopeptidase domain 30 148417 80332 hCG39255.4 ADAM33 ADAM metallopeptidase domain 33 140492 8756 hCG1789002.2 ADAM7 ADAM metallopeptidase domain 7 122603 101 hCG1816947.1 ADAM8 ADAM metallopeptidase domain 8 183965 8754 hCG1996391 ADAM9 ADAM metallopeptidase domain 9 (meltrin gamma) 129974 27299 hCG15447.3 ADAMDEC1 ADAM-like,
  • Four-Dimensional Live Imaging of Apical Biosynthetic Trafficking Reveals a Post-Golgi Sorting Role of Apical Endosomal Intermediates

    Four-Dimensional Live Imaging of Apical Biosynthetic Trafficking Reveals a Post-Golgi Sorting Role of Apical Endosomal Intermediates

    Four-dimensional live imaging of apical biosynthetic trafficking reveals a post-Golgi sorting role of apical endosomal intermediates Roland Thuenauera,b,1,2, Ya-Chu Hsua, Jose Maria Carvajal-Gonzaleza,3, Sylvie Debordea,4, Jen-Zen Chuanga, Winfried Römerc,d, Alois Sonnleitnerb, Enrique Rodriguez-Boulana,5, and Ching-Hwa Sunga,5 aMargaret M. Dyson Vision Research Institute, Weill Medical College of Cornell University, New York, NY 10065; bCenter for Advanced Bioanalysis Linz, 4020 Linz, Austria; and cInstitute of Biology II, and dBIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany Edited by Keith E. Mostov, University of California School of Medicine, San Francisco, CA, and accepted by the Editorial Board January 17, 2014 (received for review March 11, 2013) Emerging data suggest that in polarized epithelial cells newly is an important regulator of biological processes that require synthesized apical and basolateral plasma membrane proteins apical trafficking, e.g., lumen formation during epithelial tubu- traffic through different endosomal compartments en route to the logenesis (11), apical secretion of discoidal/fusiform vesicles in respective cell surface. However, direct evidence for trans-endo- bladder umbrella cells (12), and apical microvillus morphogenesis somal pathways of plasma membrane proteins is still missing and and rhodopsin localization in fly photoreceptors (13). However, the mechanisms involved are poorly understood. Here, we imaged despite the physiological importance of trans-endosomal traf- the entire biosynthetic route of rhodopsin-GFP, an apical marker in ficking, the underlying mechanisms remain largely unclear. epithelial cells, synchronized through recombinant conditional ag- Previous studies on trans-endosomal trafficking in polarized gregation domains, in live Madin-Darby canine kidney cells using epithelial cells have relied on pulse chase/cell fractionation pro- spinning disk confocal microscopy.
  • Epac2a-Null Mice Exhibit Obesity-Prone Nature More Susceptible to Leptin Resistance

    Epac2a-Null Mice Exhibit Obesity-Prone Nature More Susceptible to Leptin Resistance

    OPEN International Journal of Obesity (2017) 41, 279–288 www.nature.com/ijo ORIGINAL ARTICLE Epac2a-null mice exhibit obesity-prone nature more susceptible to leptin resistance M Hwang1,5,YGo2,5,6, J-H Park1, S-K Shin1, SE Song1, B-C Oh3, S-S Im1, I Hwang1, YH Jeon2, I-K Lee2, S Seino4 and D-K Song1 BACKGROUND: The exchange protein directly activated by cAMP (Epac), which is primarily involved in cAMP signaling, has been known to be essential for controlling body energy metabolism. Epac has two isoforms: Epac1 and Epac2. The function of Epac1 on obesity was unveiled using Epac1 knockout (KO) mice. However, the role of Epac2 in obesity remains unclear. METHODS: To evaluate the role of Epac2 in obesity, we used Epac2a KO mice, which is dominantly expressed in neurons and endocrine tissues. Physiological factors related to obesity were analyzed: body weight, fat mass, food intake, plasma leptin and adiponectin levels, energy expenditure, glucose tolerance, and insulin and leptin resistance. To determine the mechanism of Epac2a, mice received exogenous leptin and then hypothalamic leptin signaling was analyzed. RESULTS: Epac2a KO mice appeared to have normal glucose tolerance and insulin sensitivity until 12 weeks of age, but an early onset increase of plasma leptin levels and decrease of plasma adiponectin levels compared with wild-type mice. Acute leptin injection revealed impaired hypothalamic leptin signaling in KO mice. Consistently, KO mice fed a high-fat diet (HFD) were significantly obese, presenting greater food intake and lower energy expenditure. HFD-fed KO mice were also characterized by greater impairment of hypothalamic leptin signaling and by weaker leptin-induced decrease in food consumption compared with HFD-fed wild-type mice.