Skip to main content

Advertisement

SpringerLink
Log in

Expression signature of epidermolysis bullosa simplex

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Epidermolysis bullosa simplex (EBS) is a skin disorder resulting from a weakened cytoskeleton of the proliferative compartment of the epidermis, leading to cell fragility and blistering. Although many mutations have been identified in intermediate filament keratins KRT5 and KRT14, detailed pathogenic mechanisms and the way these mutations affect cell metabolism are unclear. Therefore, we performed genomic and transcriptomic study in six Canadian EBS patients and six healthy subjects. We first characterized these patients at the genetic level and identified six pathogenic mutations of which two were novel. Then, we performed an expression microarray analysis of the EBS epidermis tissue to identify potential regulatory pathways altered in this disease. Expression profiling comparisons show that 28 genes are differentially expressed in EBS patients compared to control subjects and 41 genes in severe phenotype patients (EBS-DM) compared to their paired controls. Nine genes involved in fatty acid metabolism and two genes in epidermal keratinization are common altered expressed genes (up regulated) between the two subgroups. These two biological pathways contribute both to the formation of the cell envelope barrier and seem to be defective in the severe EBS phenotype. This study identifies, for the first time, the fatty acid metabolism disruption in EBS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Baer AN, Klaus MV, Green FA (1995) Epidermal fatty acid oxygenases are activated in non-psoriatic dermatoses. J Invest Dermatol 104: 251–255

    Google Scholar 

  • Banerji S, Ni J, Wang SX et al (1999) LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J Cell Biol 144:789–801

    Article  PubMed  CAS  Google Scholar 

  • Bauer JW, Lang R, Jakab M et al (2008) Galanin family of peptides in skin function. Cell Mol Life Sci 65:1820–1825

    Article  PubMed  CAS  Google Scholar 

  • Bolling MC, Lemmink HH, Jansen GH et al (2011) Mutations in KRT5 and KRT14 cause epidermolysis bullosa simplex in 75% of the patients. Br J Dermatol 164(3):637–644

    PubMed  CAS  Google Scholar 

  • Bolstad BM, Irizarry RA, Astrand M et al (2003) A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 19:185–193

    Article  PubMed  CAS  Google Scholar 

  • Brash AR, Boeglin WE, Chang MS (1997) Discovery of a second 15S-lipoxygenase in humans. Proc Natl Acad Sci USA 94:6148–6152

    Article  PubMed  CAS  Google Scholar 

  • Cabral A, Voskamp P, Cleton-Jansen AM et al (2001) Structural organization and regulation of the small proline-rich family of cornified envelope precursors suggest a role in adaptive barrier function. J Biol Chem 276:19231–19237

    Article  PubMed  CAS  Google Scholar 

  • Chamcheu JC, Lorié EP, Akgul B et al (2009) Characterization of immortalized human epidermolysis bullosa simplex (KRT5) cell lines: trimethylamine N-oxide protects the keratin cytoskeleton against disruptive stress condition. J Dermatol Sci 53:198–206

    Article  PubMed  CAS  Google Scholar 

  • Chamcheu JC, Navsaria H, Pihl-Lundin I et al. (2011) Chemical chaperones protect epidermolysis bullosa simplex keratinocytes from heat stress-induced keratin aggregation: involvement of heat shock proteins and MAP kinases. J Invest Dermatol 14

  • Chan YM, Yu QC, LeBlanc-Straceski J et al (1994) Mutations in the non-helical linker segment L1–2 of keratin five in patients with Weber–Cockayne epidermolysis bullosa simplex. J Cell Sci 107:765–774

    PubMed  CAS  Google Scholar 

  • Cheng JB, Russell DW (2004) Mammalian wax biosynthesis. I. Identification of two fatty acyl-Coenzyme A reductases with different substrate specificities and tissue distributions. J Biol Chem 279:37789–37797

    Article  PubMed  CAS  Google Scholar 

  • Chu XY, Bleasby K, Yabut J et al (2007) Transport of the dipeptidyl peptidase-4 inhibitor sitagliptin by human organic anion transporter 3, organic anion transporting polypeptide 4C1, and multidrug resistance P-glycoprotein. J Pharmacol Exp Ther 321:673–683

    Article  PubMed  CAS  Google Scholar 

  • Ciubotaru D, Bergman R, Baty D et al (2003) Epidermolysis bullosa simplex in Israel: clinical and genetic features. Arch Dermatol 139:498–505

    Article  PubMed  CAS  Google Scholar 

  • Cottage A, Dowen S, Roberts I et al (2001) Early genetic events in HPV immortalised keratinocytes. Genes Chromosom Cancer 30:72–79

    Article  PubMed  CAS  Google Scholar 

  • Coulombe PA, Hutton ME, Letai A et al (1991) Point mutations in human keratin 14 genes of epidermolysis bullosa simplex patients: genetic and functional analyses. Cell 66:1301–1311

    Article  PubMed  CAS  Google Scholar 

  • Dallas PB, Gottardo NG, Firth MJ et al (2005) Gene expression levels assessed by oligonucleotide microarray analysis and quantitative real-time RT-PCR—how well do they correlate? BMC Genomics 27:59

    Article  Google Scholar 

  • Emtage P, Vatta P, Arterburn M et al (2006) IGFL: A secreted family with conserved cysteine residues and similarities to the IGF superfamily. Genomics 88:513–520

    Article  PubMed  CAS  Google Scholar 

  • Fine JD, Eady RA, Bauer EA et al (2000) Revised classification system for inherited epidermolysis bullosa: report of the Second International Consensus Meeting on diagnosis and classification of epidermolysis bullosa. J Am Acad Dermatol 42:1051–1066

    Article  PubMed  CAS  Google Scholar 

  • Fine JD, Eady RA, Bauer EA et al (2008) The classification of inherited epidermolysis bullosa (EB): report of the Third International Consensus Meeting on diagnosis and classification of EB. J Am Acad Dermatol 58:931–950

    Article  PubMed  Google Scholar 

  • Fogh K, Kragballe K (2000) Eicosanoids in inflammatory skin diseases. Prostaglandins Other Lipid Mediat 63:43–54

    Article  PubMed  CAS  Google Scholar 

  • García Miranda JL, Otero Gómez A et al (1983) Monosomy 22 with humoral immunodeficiency: is there an immunoglobulin chain deficit? J Med Genet 20:69–72

    Article  PubMed  Google Scholar 

  • Gautier L, Cope L, Bolstad BM et al (2004) Affy-analysis of Affymetrix GeneChip data at the probe level. Bioinformatics 20:307–315

    Article  PubMed  CAS  Google Scholar 

  • Ge L, Gordon JS, Hsuan C, Stenn K et al (2003) Identification of the delta-6 desaturase of human sebaceous glands: expression and enzyme activity. J Invest Dermatol 120:707–714

    Article  PubMed  CAS  Google Scholar 

  • Gregory SG, Barlow KF, McLay KE et al (2006) The DNA sequence and biological annotation of human chromosome 1. Nature 441:315–321

    Article  PubMed  CAS  Google Scholar 

  • Gregory Alvord W, Roayaei JA, Quinones OA et al (2007) A microarray analysis for differential gene expression in the soybean genome using Bioconductor and R. Brief Bioinform 8:415–431

    Article  PubMed  CAS  Google Scholar 

  • Hobart MJ, Rabbitts TH, Goodfellow PN et al (1981) Immunoglobulin heavy chain genes in humans are located on chromosome. Ann Hum Genet 45:331–335

    Article  PubMed  CAS  Google Scholar 

  • Hohl D (1990) A new star in the heavens of epidermal proteins: loricrin—what is it? Hautarzt 41:299–301

    PubMed  CAS  Google Scholar 

  • Holmes RS (2010) Comparative genomics and proteomics of vertebrate diacylglycerol acyltransferase (DGAT), acyl CoA wax alcohol acyltransferase (AWAT) and monoacylglycerol acyltransferase (MGAT). Comp Biochem Physiol Part D Genomics Proteomics 5:45–54

    Article  PubMed  Google Scholar 

  • Hsieh JC, Kodjabachian L, Rebbert ML et al (1999) A new secreted protein that binds to Wnt proteins and inhibits their activities. Nature 398:431–436

    Article  PubMed  CAS  Google Scholar 

  • Huang SH, Pittler SJ, Huang X et al (1995) Autosomal recessive retinitis pigmentosa caused by mutations in the alpha subunit of rod cGMP phosphodiesterase. Nat Genet 11:468–471

    Article  PubMed  CAS  Google Scholar 

  • Humphries MM, Mansergh FC, Kiang AS et al (1996) Three keratin gene mutations account for the majority of dominant simplex epidermolysis bullosa cases within the population of Ireland. Hum Mutat 8:57–63

    Article  PubMed  CAS  Google Scholar 

  • Irvine AD, McLean WH (1999) Human keratin diseases: the increasing spectrum of disease and subtlety of the phenotype–genotype correlation. Br J Dermatol 140:815–828

    Article  PubMed  CAS  Google Scholar 

  • Iversen L, Kragballe K (2000) Arachidonic acid metabolism in skin health and disease. Prostaglandins Other Lipid Mediat 63:25–42

    Article  PubMed  CAS  Google Scholar 

  • Iwata A, Maruyama M, Akagi T et al (2003) Alpha-synuclein degradation by serine protease neurosin: implication for pathogenesis of synucleinopathies. Hum Mol Genet 12:2625–2635

    Article  PubMed  CAS  Google Scholar 

  • Jobard F, Lefèvre C, Karaduman A et al (2002) Lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) are mutated in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17p13.1. Hum Mol Genet 11:107–113

    Article  PubMed  CAS  Google Scholar 

  • Jones JM, Morrell JC, Gould SJ (2000) Identification and characterization of HAOX1, HAOX2, and HAOX3, three human peroxisomal 2-hydroxy acid oxidases. J Biol Chem 275:12590–12597

    Article  PubMed  CAS  Google Scholar 

  • Jonsson AK, Hyldig-Nielsen JJ, Servenius B et al (1987) Class II genes of the human major histocompatibility complex. Comparisons of the DQ and DX alpha and beta genes. J Biol Chem 262:8767–8777

    PubMed  CAS  Google Scholar 

  • Leonard AE, Kelder B, Bobik EG et al (2000) cDNA cloning and characterization of human Delta5-desaturase involved in the biosynthesis of arachidonic acid. Biochem J 347:719–724

    Article  PubMed  CAS  Google Scholar 

  • Liovic M, D’Alessandro M, Tomic-Canic M et al (2009) Severe keratin 5 and 14 mutations induce down-regulation of junction proteins in keratinocytes. Exp Cell Res 315:2995–3003

    Article  PubMed  CAS  Google Scholar 

  • Lu H, Chen J, Planko L et al (2007) Induction of inflammatory cytokines by a keratin mutation and their repression by a small molecule in a mouse model for EBS. J Invest Dermatol 127:2781–2789

    PubMed  CAS  Google Scholar 

  • Martinat C, Bacci JJ, Leete T et al (2006) Cooperative transcription activation by Nurr1 and Pitx3 induces embryonic stem cell maturation to the midbrain dopamine neuron phenotype. Proc Natl Acad Sci USA 103:2874–2879

    Article  PubMed  CAS  Google Scholar 

  • Matoltsy AG, Matoltsy MN (1966) The membrane protein of horny cells. J Invest Dermatol 46:127–129

    PubMed  CAS  Google Scholar 

  • Modyanov NN, Petrukhin KE, Sverdlov VE et al (1991) The family of human Na, K-ATPase genes. ATP1AL1 gene is transcriptionally competent and probably encodes the related ion transport ATPase. FEBS Lett 278:91–94

    Article  PubMed  CAS  Google Scholar 

  • Moreau A, Téruel C, Beylot M et al (2009) A novel pregnane X receptor and S14-mediated lipogenic pathway in human hepatocyte. Hepatology 49:2068–2079

    Article  PubMed  CAS  Google Scholar 

  • Novak JP, Sladek R, Hudson TJ (2002) Characterization of variability in large-scale gene expression data: implications for study design. Genomics 79:104–113

    Article  PubMed  CAS  Google Scholar 

  • Oh SW, Lee JS, Kim MY et al (2007) Novel keratin 5 mutations in epidermolysis bullosa simplex: cases with unusual genotype–phenotype correlation. J Dermatol Sci 48:229–232

    Article  PubMed  CAS  Google Scholar 

  • Okazaki K, Sagata N (1995) The Mos/MAP kinase pathway stabilizes c-Fos by phosphorylation and augments its transforming activity in NIH 3T3 cells. EMBO J 14:5048–5059

    PubMed  CAS  Google Scholar 

  • Oxholm A, Oxholm P, da Cunha Bang F et al (1990) Abnormal essential fatty acid metabolism in Darier’s disease. Arch Dermatol 126:1308–1311

    Article  PubMed  CAS  Google Scholar 

  • Plowman GD, Green JM, McDonald VL et al (1990) The amphiregulin gene encodes a novel epidermal growth factor-related protein with tumor-inhibitory activity. Mol Cell Biol 10:1969–1981

    PubMed  CAS  Google Scholar 

  • Puglielli L, Konopka G, Pack-Chung E et al (2001) Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid beta-peptide. Nat Cell Biol 3:905–912

    Article  PubMed  CAS  Google Scholar 

  • Qi X, Hosoi T, Okuma Y et al (2004) Sodium 4-phenylbutyrate protects against cerebral ischemic injury. Mol Pharmacol 66:899–908

    Article  PubMed  CAS  Google Scholar 

  • Renkema GH, Boot RG, Au FL et al (1998) Chitotriosidase, a chitinase, and the 39-kDa human cartilage glycoprotein, a chitin-binding lectin, are homologues of family 18 glycosyl hydrolases secreted by human macrophages. Eur J Biochem 251:504–509

    Article  PubMed  CAS  Google Scholar 

  • Rice RH, Green H (1977) The cornified envelope of terminally differentiated human epidermal keratinocytes consists of cross-linked protein. Cell 11:417–422

    Article  PubMed  CAS  Google Scholar 

  • Rogers MA, Winter H, Langbein L et al (2004) The human type I keratin gene family: characterization of new hair follicle specific members and evaluation of the chromosome 17q21.2 gene domain. Differentiation 72:527–540

    Article  PubMed  CAS  Google Scholar 

  • Rogers MA, Edler L, Winter H et al (2005) Characterization of new members of the human type II keratin gene family and a general evaluation of the keratin gene domain on chromosome 12q13.13. J Invest Dermatol 124:536–544

    Article  PubMed  CAS  Google Scholar 

  • Roth W, Reuter U, Wohlenberg C et al (2009) Cytokines as genetic modifiers in K5−/− mice and in human epidermolysis bullosa simplex. Hum Mutat 30:832–841

    Article  PubMed  CAS  Google Scholar 

  • Rugg EL, Horn HM, Smith FJ et al (2007) Epidermolysis bullosa simplex in Scotland caused by a spectrum of keratin mutations. J Invest Dermatol 127:574–580

    Article  PubMed  CAS  Google Scholar 

  • Sääf AM, Tengvall-Linder M, Chang HY et al (2008) Global expression profiling in atopic eczema reveals reciprocal expression of inflammatory and lipid genes. PLoS One 3:e4017

    Article  PubMed  Google Scholar 

  • Sasaki Y, Shimizu H, Akiyama M et al (1998) Abnormalities of basal cell keratin in epidermolysis bullosa simplex do not affect the statement patterns of suprabasal keratins and cornified cell envelope proteins. Arch Dermatol Res 290:591–597

    Article  PubMed  CAS  Google Scholar 

  • Schaffer JE, Lodish HF (1994) Expression cloning and characterization of a novel adipocyte long chain fatty acid transport protein. Cell 79:427–436

    Article  PubMed  CAS  Google Scholar 

  • Schramm L, Pendergrast PS, Sun Y et al (2000) Different human TFIIIB activities direct RNA polymerase III transcription from TATA-containing and TATA-less promoters. Genes Dev 14:2650–2663

    Article  PubMed  CAS  Google Scholar 

  • Schuilenga-Hut PH, Vlies P et al (2003) Mutation analysis of the entire keratin 5 and 14 genes in patients with epidermolysis bullosa simplex and identification of novel mutations. Hum Mutat 21:447

    Article  PubMed  Google Scholar 

  • Smyth GK (2004) Linear models and empirical Bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 3: Article3

  • Stark K, Törmä H, Oliw EH (2006) Co-localization of COX-2, CYP4F8, and mPGES-1 in epidermis with prominent expression of CYP4F8 mRNA in psoriatic lesions. Prostaglandins Other Lipid Mediat 79:114–125

    Article  PubMed  CAS  Google Scholar 

  • Steinberg SJ, Morgenthaler J, Heinzer AK et al (2000) Very long-chain acyl-CoA synthetases. Human “bubblegum” represents a new family of proteins capable of activating very long-chain fatty acids. J Biol Chem 275:35162–35169

    Article  PubMed  CAS  Google Scholar 

  • Steinert PM, Marekov LN (1999) Initiation of assembly of the cell envelope barrier structure of stratified squamous epithelia. Mol Biol Cell 10:4247–4261

    PubMed  CAS  Google Scholar 

  • Steinert PM, Parry DA, Marekov LN (2003) Trichohyalin mechanically strengthens the hair follicle: multiple cross-bridging roles in the inner root shealth. J Biol Chem 278:41409–41419

    Article  PubMed  CAS  Google Scholar 

  • Stephens K, Ehrlich P, Weaver M et al (1997) Primers for exon-specific amplification of the KRT5 gene: identification of novel and recurrent mutations in epidermolysis bullosa simplex patients. J Invest Dermatol 108:349–353

    Article  PubMed  CAS  Google Scholar 

  • Szeverenyi I, Cassidy AJ, Chung CW et al (2008) The Human Intermediate Filament Database: comprehensive information on a gene family involved in many human diseases. Hum Mutat 29:351–360

    Article  PubMed  CAS  Google Scholar 

  • Teglund S, Olsen A, Khan WN et al (1994) The pregnancy-specific glycoprotein (PSG) gene cluster on human chromosome 19: fine structure of the 11 PSG genes and identification of 6 new genes forming a third subgroup within the carcinoembryonic antigen (CEA) family. Genomics 23:669–684

    Article  PubMed  CAS  Google Scholar 

  • Turkish AR, Henneberry AL, Cromley D et al (2005) Identification of two novel human acyl-CoA wax alcohol acyltransferases: members of the diacylglycerol acyltransferase 2 (DGAT2) gene superfamily. J Biol Chem 280:14755–14764

    Article  PubMed  CAS  Google Scholar 

  • Virolle T, Krones-Herzig A, Baron V (2003) Egr1 promotes growth and survival of prostate cancer cells. Identification of novel Egr1 target genes. J Biol Chem 278:11802–11810

    Article  PubMed  CAS  Google Scholar 

  • Wang Z, Hao Y, Lowe AW (2008) The adenocarcinoma-associated antigen, AGR2, promotes tumor growth, cell migration, and cellular transformation. Cancer Res 68:492–497

    Article  PubMed  CAS  Google Scholar 

  • Westerberg R, Månsson JE, Golozoubova V et al (2006) ELOVL3 is an important component for early onset of lipid recruitment in brown adipose tissue. J Biol Chem 281:4958–4968

    Article  PubMed  CAS  Google Scholar 

  • Wu D, Govindasamy L, Lian W et al (2003) Structure of human carnitine acetyltransferase. Molecular basis for fatty acyl transfer. J Biol Chem 278:13159–13165

    Article  PubMed  CAS  Google Scholar 

  • Yahagi S, Shibuya K, Obayashi I et al (2004) Identification of two novel clusters of ultrahigh-sulfur keratin-associated protein genes on human chromosome 11. Biochem Biophys Res Commun 318:655–664

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto M, Bharti A, Li Y et al (1997) Interaction of the DF3/MUC1 breast carcinoma-associated antigen and beta-catenin in cell adhesion. J Biol Chem 272:12492–12494

    Article  PubMed  CAS  Google Scholar 

  • Yang T, Espenshade PJ, Wright ME et al (2002) Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. Cell 110:489–500

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank the patients and their families for their enthusiastic collaboration. This work was supported by Le Groupe Riverin Inc and by La Campagne majeure de développement de l’Université du Québec à Chicoutimi. The authors thank Claude Belleville and Julie Duval for their invaluable help in recruiting and evaluating the subjects for the study, Anne-Marie Madore for her precious technical support, the technical staff at the McGill University and Genome Quebec Innovation Centre for microarray hybridization as well as the technical staff at the Sequencing Facility of the CHUL/CHUQ.

Conflict of interest

No conflict of interest.

Author information

Authors and Affiliations

  1. Département des sciences fondamentales, Université du Québec à Chicoutimi, Saguenay, Canada

    Mbarka Bchetnia, Marie-Lou Tremblay, Valérie Legendre-Guillemin & Catherine Laprise

  2. Centre de santé et de services sociaux de Chicoutimi, Saguenay, Canada

    Georgette Leclerc, Audrey Dupérée & Charles Morin

  3. Hôpital Sainte-Justine, Montréal, Canada

    Julie Powell & Catherine McCuaig

Authors
  1. Mbarka Bchetnia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marie-Lou Tremblay
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Georgette Leclerc
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Audrey Dupérée
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Julie Powell
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Catherine McCuaig
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Charles Morin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Valérie Legendre-Guillemin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Catherine Laprise
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Catherine Laprise.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bchetnia, M., Tremblay, ML., Leclerc, G. et al. Expression signature of epidermolysis bullosa simplex. Hum Genet 131, 393–406 (2012). https://doi.org/10.1007/s00439-011-1077-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-011-1077-7

Keywords

Search

Navigation