DOCSLIB.ORG

ESGCT XXV Anniversary Congress in Collaboration with the German

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
ESGCT XXV Anniversary Congress in Collaboration with the German ESGCT XXV Anniversary Congress in Collaboration with the German Society for Gene Therapy October 17–20, 2017 Berlin, Germany Downloaded by 86.2.119.197 from online.liebertpub.com at 12/11/17. For personal use only. HUMAN GENE THERAPY 28:A2–A125 (2017) ª Mary Ann Liebert, Inc. DOI: 10.1089/hum.2017.29055.abstracts Selected Oral Presentations OR01 Institute, Woolloongabba, Queensland 4102, Australia. 3: Leibniz Research Laboratories for Biotechnology and Generation of three-dimensional human artificial skeletal Artificial Organs (LEBAO), Department of Cardiac, Thoracic, muscle tissue from iPS cells enables complex disease Transplantation, and Vascular Surgery; Hannover Medical modelling for muscular dystrophy School, D-30625 Hannover, Germany 4: Department of Human S M Maffioletti1 S Sarcar1 A Henderson1 I Mannhardt2 DNA Variability, GENYO, PTS Granada, 18016 Granada, L Pinton1 L A Moyle1 H Steele-Stallard1 O Cappellari4 Spain. 5: Max Delbru¨ck Center for Molecular Medicine, K E Wells4 M Ragazzi1 W Wang1 P Zammit3 D J Wells4 D-13125 Berlin, Germany 6: Fachbereich Mathematik, T Eschenhagen2 F S Tedesco1 Naturwissenschaften & Informatik, Technische Hochschule Mittelhessen, D-35390 Gießen, Germany. 1: Department of Cell and Developmental Biology, University College London, WC1E 6DE London, UK 2: Department of Human induced pluripotent stem cells (hiPSCs) hold substan- Experimental Pharmacology and Toxicology, University Medical tial promise for regenerative medicine. However, reprogramming Center Hamburg Eppendorf (UKE), 20246 Hamburg and DZHK and subsequent hiPSC cultivation can result in genetic and epi- (German Centre for Cardiovascular Research), partner site genetic abnormalities, and mutations that can undermine their use Hamburg/Kiel/Lu¨beck, Germany 3: Randall Division of Cell and in regenerative medicine, because they compromise biosafety of Molecular Biophysics, King’s College London, SE1 1UL London, hiPSC-derived differentiated cells. Activation of endogenous UK 4: Department of Comparative Biomedical Sciences, Royal mobile retrotransposons LINE-1 (Long Interspersed Element-1, Veterinary College, NW1 0TU London, UK L1), Alu and SVA can cause such mutations. In differentiated cells, L1 is suppressed by methylation of its CpG-rich promoter. Generating artificial human skeletal muscle would be instru- We show that reprogramming triggers transcription of L1 ele- mental for investigating skeletal muscle pathology and therapy. ments via demethylation and that reprogramming factors further However, current bioengineering platforms are challenged by the upregulate L1 promoter activity. By applying retrotransposon limited expansion potential and differentiation ability of tissue- capture-sequencing to 8 hiPSC lines and their parental cells, we derived myogenic cells. Here, we describe the generation of three- found that L1 transcriptional activation causes new L1-mediated dimensional artificial skeletal muscle tissue from human embryonic genomic insertions: We identified numerous L1, Alu and SVA de and induced pluripotent stem cells, including cells from patients novo retrotransposition events that occurred during reprogram- with Duchenne, limb-girdle and congenital muscular dystrophies. ming and hiPSC cultivation. We estimated *1L1denovoin- Skeletal myogenic differentiation of pluripotent cells was induced sertion per hiPSC, constituting a mutagenic load per cell as within hydrogels under tension to provide alignment. Artificial represented by exogenously applied integrating gene therapy muscles recapitulated characteristics of human skeletal muscle tis- vectors. *50% of all new retrotransposition events occurred in sue and could be implanted into immunodeficient mice. Im- transcribed protein-coding genes, including genes involved in portantly, they enabled in vitro modelling of pathological hallmarks oncogenesis, development or signal transduction. We demonstrate of some forms of muscular dystrophy with higher fidelity than interference of new L1 insertions with host gene expression in standard bi-dimensional cultures. Finally, we show generation of hiPSCs. Consistently, analysis of 1800 marked L1 insertions re- complex multicellular constructs, all human iPS cell-derived, con- Downloaded by 86.2.119.197 from online.liebertpub.com at 12/11/17. For personal use only. sulting from mobilization of genetically engineered L1 reporter taining isogenic cell types present in normal skeletal muscle, such elements during hiPSC cultivation, confirmed that *50% of all as vascular endothelial cells and pericytes. These results lay the insertions accumulate in host genes. L1 de novo insertions were foundation for a human skeletal muscle organoid-like platform for also enriched at active transcriptional start sites where they might regenerative medicine, disease modelling and therapy development. affect host gene expression. Our findings imply consequences for the biological safety of hiPSC-derived cell therapies. OR02 Reprogramming triggers mobilisation of endogenous OR03 retrotransposons in human induced pluripotent stem cells with genotoxic effects on host gene expression Dynamic remodelling of neural cellular and extracellular signatures depicted in 3D in vitro differentiation S Jung-Klawitter1 N V Fuchs15K R Upton2 A Fro¨mmrich3 of human iPSC-derived NSC C Miskey1 M Mun˜oz-Lopez4 R Shukla2 J Wang5 A Sebe1 S Merkert3 A Bock1 U Held1 M Menzel6 A Gogol-Do¨ring6 D Sima˜o1 A P Terrasso1 M M Silva1 F Arez1 M F Sousa1 A Haase3 Z Izsva´k5 Z Ivics1 U Martin3 J Garcia-Perez4 N Raimundo2 P Gomes-Alves1 E J Kremer3 P M Alves1 C Brito1 G J Faulkner2 G G Schumann1 1: iBET, Instituto de Biologia Experimental e Tecnolo´gica, 1: Division of Medical Biotechnology, Paul-Ehrlich-Institute, Oeiras, Portugal and Instituto de Tecnologia Quı´mica e D-63225 Langen, Germany. 2: Mater Medical Research Biolo´gica Anto´nio Xavier, Universidade Nova de Lisboa, Oeiras, A2 SELECTED ORAL PRESENTATIONS A3 Portugal 2: Universita¨tsmedizin Go¨ttingen, Institut fu¨r photoreceptor genesis. Immunohistological examination of the Zellbiochemie, Go¨ttingen, Germany 3: Institut de Ge´ne´tique organoids at different culture time points revealed that the or- Mole´culaire de Montpellier, CNRS UMR 5535, Montpellier, ganoids recapitulate the different stages of retinogenesis and France and Universite´ de Montpellier, Montpellier, France confirmed the production of a large number of photorecep- tors. This cell line can now serve to study human photoreceptor Brain microenvironment plays an important role in devel- development and pathologies as well as to produce a large opment and function. Disruption of its homeostasis is often photoreceptor number for drug screening and transplantation related to pathological conditions, as the lysosomal storage studies. disease mucopolysaccharidosis type VII (MPS VII), caused by deficient b-glucuronidase activity. We hypothesized that 3D differentiation of human neural stem cells (hNSC) neu- rospheres in perfusion stirred-tank bioreactors could sustain microenvironment remodeling, recapitulating key cell-ECM interactions. Differentiation of hNSC derived from induced OR05 pluripotent stem cells (hiPSC-NSC), both from healthy do- AAV-mediated CYP46A1 gene therapy nors and a MPS VII patient, were shown to recapitulate for Huntington’s disease neurogenic developmental pathways, generating tissue-like N Cartier1 S Alves2 W Christaller3 E Subashi1 R Kacher4 3D structures with neuronal, astroglial and oligodendroglial 5 5 3 4 4 cells. Changes in neural microenvironment during differen- A Lamazie`re G Despres F Saudou J Caboche S Betuing tiation, namely at cell membrane and ECM composition, were 1: INSERM/CEA UMR1169, MIRCEN CEA and Universite’ addressed using quantitative transcriptomic (NGS) and pro- Paris-Sud, Universite’ Paris Saclay, 91400 Orsay, France teomic data (SWATH-MS). Data revealed a significant enrich- 2: BrainVectis Therapeutics, 18 route du Panorama 92 265 ment in structural proteoglycans, such as neurocan, versican, Fontenay-aux-Roses Cedex, France 3: INSERM U1216 and brevican and tenascin C, along with downregulation of basement University Grenoble Alpes, Grenoble Institut des Neurosciences, membrane constituents (e.g., laminins, collagens and fibrillins). GIN, 38000 Grenoble, France 4: Neuronal Signaling and Gene In MPS VII cells, important disease hallmarks were recapitu- Regulation, Neurosciences Paris Seine, Institute of Biology lated, as the accumulation of glycosaminoglycans. Glial differ- Paris-Seine, Sorbonne Universite’s, UPMC Universite’ Pierre et entiation was increased and alterations in neuronal activity and Marie Curie-Paris 6, INSERM/UMR-S 1130, CNRS/UMR 8246, connectivity were observed. In summary, we demonstrated that 75005 Paris, France 5: Laboratory of Mass Spectrometry, neural cellular and extracellular developmental features are re- INSERM ERL 1157, CNRS UMR 7203 LBM, Sorbonne capitulated in hiPSC-NSC-derived neural microtissues. These Universite’s- Universite’ Pierre et Marie Curie-Paris 6, CHU can be valuable in vitro models to address molecular defects Saint-Antoine, 75012 Paris, France associated with neurological disorders that affect the microen- vironment homeostasis, as MPS VII. Brain cholesterol homeostasis defects in the adult brain are linked to neurodegenerative diseases, such as Niemann-Pick C, Alzheimer and Huntington’s diseases (HD). In HD, cho- lesterol homeostasis defects involve a general perturbation in OR04 the expression of cholesterol biosynthesis enzymes. 24S- hydroxycholesterol (24OH-Chol), the catabolite
Load more

Recommended publications
  • Mutations in SERPINB7, Encoding a Member of the Serine Protease Inhibitor Superfamily, Cause Nagashima-Type Palmoplantar Keratosis
    REPORT Mutations in SERPINB7, Encoding a Member of the Serine Protease Inhibitor Superfamily, Cause Nagashima-type Palmoplantar Keratosis Akiharu Kubo,1,2,3,* Aiko Shiohama,1,4 Takashi Sasaki,1,2,3 Kazuhiko Nakabayashi,5 Hiroshi Kawasaki,1 Toru Atsugi,1,6 Showbu Sato,1 Atsushi Shimizu,7 Shuji Mikami,8 Hideaki Tanizaki,9 Masaki Uchiyama,10 Tatsuo Maeda,10 Taisuke Ito,11 Jun-ichi Sakabe,11 Toshio Heike,12 Torayuki Okuyama,13 Rika Kosaki,14 Kenjiro Kosaki,15 Jun Kudoh,16 Kenichiro Hata,5 Akihiro Umezawa,17 Yoshiki Tokura,11 Akira Ishiko,18 Hironori Niizeki,19 Kenji Kabashima,9 Yoshihiko Mitsuhashi,10 and Masayuki Amagai1,2,4 ‘‘Nagashima-type’’ palmoplantar keratosis (NPPK) is an autosomal recessive nonsyndromic diffuse palmoplantar keratosis characterized by well-demarcated diffuse hyperkeratosis with redness, expanding on to the dorsal surfaces of the palms and feet and the Achilles tendon area. Hyperkeratosis in NPPK is mild and nonprogressive, differentiating NPPK clinically from Mal de Meleda. We performed whole-exome and/or Sanger sequencing analyses of 13 unrelated NPPK individuals and identified biallelic putative loss-of-function mutations in SERPINB7, which encodes a cytoplasmic member of the serine protease inhibitor superfamily. We identified a major caus- ative mutation of c.796C>T (p.Arg266*) as a founder mutation in Japanese and Chinese populations. SERPINB7 was specifically present in the cytoplasm of the stratum granulosum and the stratum corneum (SC) of the epidermis. All of the identified mutants are predicted to cause premature termination upstream of the reactive site, which inhibits the proteases, suggesting a complete loss of the protease inhibitory activity of SERPINB7 in NPPK skin.
    [Show full text]
  • The P63 Target HBP1 Is Required for Skin Differentiation and Stratification
    Cell Death and Differentiation (2010) 17, 1896–1907 & 2010 Macmillan Publishers Limited All rights reserved 1350-9047/10 $32.00 www.nature.com/cdd The p63 target HBP1 is required for skin differentiation and stratification S Borrelli1, E Candi2,BHu3, D Dolfini1, M Ravo4, OMV Grober4, A Weisz4,5, GP Dotto3, G Melino2,6, MA Vigano` 1 and R Mantovani*,1 Genetic experiments established that p63 is crucial for the development and maintenance of pluristratified epithelia. In the RNA interference (RNAi) screening for targets of p63 in keratinocytes, we identified the transcription factor, High Mobility Group (HMG) box protein 1 (HBP1). HBP1 is an HMG-containing repressor transiently induced during differentiation of several cell lineages. We investigated the relationship between the two factors: using RNAi, overexpression, chromatin immunoprecipita- tions and transient transfections with reporter constructs, we established that HBP1 is directly repressed by p63. This was further confirmed in vivo by evaluating expression in p63 knockout mice and in transgenics expressing p63 in basal keratinocytes. Consistent with these findings, expression of HBP1 increases upon differentiation of primary keratinocytes and HaCaT cells in culture, and it is higher in the upper layers of human skin. Inactivation of HBP1 by RNAi prevents differentiation of keratinocytes and stratification of organotypic skin cultures. Finally, we analyzed the keratinocyte transcriptomes after HBP1 RNAi; in addition to repression of growth-promoting genes, unexpected activation of differentiation genes was uncovered, coexisting with repression of other genes involved in epithelial cornification. Our data indicate that suppression of HBP1 is part of the growth-promoting strategy of p63 in the lower layers of epidermis and that HBP1 temporally coordinates expression of genes involved in stratification, leading to the formation of the skin barrier.
    [Show full text]
  • Spink2 Modulates Apoptotic Susceptibility and Is a Candidate Gene in the Rgcs1 QTL That Affects Retinal Ganglion Cell Death After Optic Nerve Damage
    Spink2 Modulates Apoptotic Susceptibility and Is a Candidate Gene in the Rgcs1 QTL That Affects Retinal Ganglion Cell Death after Optic Nerve Damage Joel A. Dietz1., Margaret E. Maes1., Shuang Huang2, Brian S. Yandell2, Cassandra L. Schlamp1, Angela D. Montgomery1, R. Rand Allingham3, Michael A. Hauser3, Robert W. Nickells1* 1 Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, United States of America, 2 Department of Biostatistics, University of Wisconsin, Madison, Wisconsin, United States of America, 3 Center for Human Genetics, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America Abstract The Rgcs1 quantitative trait locus, on mouse chromosome 5, influences susceptibility of retinal ganglion cells to acute damage of the optic nerve. Normally resistant mice (DBA/2J) congenic for the susceptible allele from BALB/cByJ mice exhibit susceptibility to ganglion cells, not only in acute optic nerve crush, but also to chronic inherited glaucoma that is characteristic of the DBA/2J strain as they age. SNP mapping of this QTL has narrowed the region of interest to 1 Mb. In this region, a single gene (Spink2) is the most likely candidate for this effect. Spink2 is expressed in retinal ganglion cells and is increased after optic nerve damage. This gene is also polymorphic between resistant and susceptible strains, containing a single conserved amino acid change (threonine to serine) and a 220 bp deletion in intron 1 that may quantitatively alter endogenous expression levels between strains. Overexpression of the different variants of Spink2 in D407 tissue culture cells also increases their susceptibility to the apoptosis-inducing agent staurosporine in a manner consistent with the differential susceptibility between the DBA/2J and BALB/cByJ strains.
    [Show full text]
  • Serine Protease Activity and Residual LEKTI Expression
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector See related commentary on page 1622 ORIGINAL ARTICLE Serine Protease Activity and Residual LEKTI Expression Determine Phenotype in Netherton Syndrome Jean-Pierre Hachem1,2, Fredrik Wagberg3, Matthias Schmuth4, Debra Crumrine2, Willy Lissens5, Arumugam Jayakumar6, Evi Houben1, Theodora M. Mauro2,Go¨ran Leonardsson3, Maria Brattsand7, Torbjorn Egelrud7, Diane Roseeuw1, Gary L. Clayman6, Kenneth R. Feingold2, Mary L. Williams2 and Peter M. Elias2 Mutations in the SPINK5 gene encoding the serine protease (SP) inhibitor, lymphoepithelial-Kazal-type 5 inhibitor (LEKTI), cause Netherton syndrome (NS), a life-threatening disease, owing to proteolysis of the stratum corneum (SC). We assessed here the basis for phenotypic variations in nine patients with ‘‘mild’’, ‘‘moderate’’, and ‘‘severe’’ NS. The magnitude of SP activation correlated with both the barrier defect and clinical severity, and inversely with residual LEKTI expression. LEKTI co-localizes within the SC with kallikreins 5 and 7 and inhibits both SP. The permeability barrier abnormality in NS was further linked to SC thinning and proteolysis of two lipid hydrolases (b-glucocerebrosidase and acidic sphingomyelinase), with resultant disorganization of extracellular lamellar membranes. SC attenuation correlated with phenotype-dependent, SP activation, and loss of corneodesmosomes, owing to desmoglein (DSG)1 and desmocollin (DSC)1 degradation. Although excess SP activity extended into the nucleated layers in NS, degrading desmosomal mid-line structures with loss of DSG1/DSC1, the integrity of the nucleated epidermis appears to be maintained by compensatory upregulation of DSG3/DSC3. Maintenance of sufficient permeability barrier function for survival correlated with a compensatory acceleration of lamellar body secretion, providing a partial permeability barrier in NS.
    [Show full text]
  • Correlation Between SPINK5 Gene Mutations and Clinical
    ORIGINAL ARTICLE Correlation between SPINK5 Gene Mutations and Clinical Manifestations in Netherton Syndrome Patients Nahoko Komatsu1,2,3, Kiyofumi Saijoh4, Arumugam Jayakumar5, Gary L. Clayman5, Mikiko Tohyama6, Yasushi Suga7, Yuki Mizuno7, Katsuhiko Tsukamoto8, Katsushige Taniuchi9, Kazuhiko Takehara3 and Eleftherios P. Diamandis1,2 Netherton syndrome (NS) is a congenital ichthyosiform dermatosis caused by serine protease inhibitor Kazal- type 5 (SPINK5) mutations. Tissue kallikreins (KLKs) and lymphoepithelial Kazal-type-related inhibitor (LEKTI) (SPINK5 product) may contribute to the balance of serine proteases/inhibitors in skin and influence skin barrier function and desquamation. SPINK5 mutations, causing NS, lead to truncated LEKTI; each NS patient possesses LEKTI of a different length, depending on the location of mutations. This study aims to elucidate genotype/ phenotype correlations in Japanese NS patients and to characterize the functions of each LEKTI domain. Since we were unable to demonstrate truncated proteins in tissue from patients with NS, we used recombinant protein to test the hypothesis that the length of LEKTI correlated with protease inhibitory activity. Genotype/ phenotype correlations were observed with cutaneous severity, growth retardation, skin infection, stratum corneum (SC) protease activities, and KLK levels in the SC. Predominant inhibition by LEKTI domains against overall SC protease activities was trypsin-like (Phe-Ser-Arg-) activity by LEKTI domains 6–12, plasmin- and trypsin-like (Pro-Phe-Arg-) activities by domains 12–15, chymotrypsin-like activity by all domains, and furin-like activity by none. KLK levels were significantly elevated in the SC and serum of NS patients. These data link LEKTI domain deficiency and clinical manifestations in NS patients and pinpoints to possibilities for targeted therapeutic interventions.
    [Show full text]
  • Allergic Manifestations of Primary Immunodeficiency Diseases and Its Treatment Approaches
    Online - 2455-3891 Vol 11, Issue 11, 2018 Print - 0974-2441 Review Article ALLERGIC MANIFESTATIONS OF PRIMARY IMMUNODEFICIENCY DISEASES AND ITS TREATMENT APPROACHES OKSANA BOYARCHUK* Department of Children’s Diseases and Pediatric Surgery, I. Horbachevsky Ternopil State Medical University, Ternopil City, Ukraine. Email: [email protected] Received: 11 August 2018, Revised and Accepted: 27 September 2018 ABSTRACT Allergic manifestations are one of the clinical signs of primary immunodeficiency diseases (PID). In this review, the common allergic manifestations of PID are summarized, and their main differential characteristics and treatment approaches are outlined. Allergic manifestations occur more often in patients with combined immunodeficiencies with or without associated or syndromic features. In patients with PID they usually are present in the 1st year of life, may be among the first symptoms of PID, and are commonly manifested by eczema and increased immunoglobulin IgG levels. Often the skin barrier function is not impaired in patients with eczema and PID, although some diseases (such as Comel-Netherton syndrome) do affect skin barrier function. There is usually no correlation between IgE levels and the severity of allergic skin manifestations. Allergic-like manifestations in PID patients include urticaria-like rash and angioedema. Urticaria-like rash is associated with autoinflammatory disorders, which are commonly accompanied by fever, and caused by a neutrophilic infiltrate in the dermis. Angioedema in hereditary angioedema patients is caused by high bradykinin production. Early differentiation of allergic manifestations in PID from atopic dermatitis and other atopic conditions is very difficult; however, it is very important because it influences on treatment methods. A multidisciplinary approach to the management of PID patients, with the involvement of immunologists, allergists, and formulation of appropriate treatment improve the prognosis and quality of life of the PID patients.
    [Show full text]
  • Transgenic Kallikrein 5 Mice Reproduce Major Cutaneous and Systemic Hallmarks of Netherton Syndrome
    Published February 17, 2014 Article Transgenic kallikrein 5 mice reproduce major cutaneous and systemic hallmarks of Netherton syndrome Laetitia Furio,1,2 Simon de Veer,1,2 Madeleine Jaillet,1,2 Anais Briot,2 Aurelie Robin,2 Celine Deraison,2 and Alain Hovnanian1,2,3 1Université Paris Descartes-Sorbonne Paris Cité, 75006 Paris, France 2INSERM UMR 1163, Laboratory of Genetic Skin Diseases, Imagine Institute, 75015 Paris, France 3Department of Genetics, Necker Hospital, 75015 Paris, France Netherton syndrome (NS) is a severe genetic skin disease in which absence of a key Downloaded from protease inhibitor causes congenital exfoliative erythroderma, eczematous-like lesions, and atopic manifestations. Several proteases are overactive in NS, including kallikrein- related peptidase (KLK) 5, KLK7, and elastase-2 (ELA2), which are suggested to be part of a proteolytic cascade initiated by KLK5. To address the role of KLK5 in NS, we have generated a new transgenic murine model expressing human KLK5 in the granular layer of the epidermis (Tg-KLK5). Transgene expression resulted in increased proteolytic activity attributable to KLK5 and its downstream targets KLK7, KLK14, and ELA2. Tg-KLK5 mice jem.rupress.org developed an exfoliative erythroderma with scaling, growth delay, and hair abnormalities. The skin barrier was defective and the stratum corneum was detached through desmo- somal cleavage. Importantly, Tg-KLK5 mice displayed cutaneous and systemic hallmarks of severe inflammation and allergy with pruritus. The skin showed enhanced expression of inflammatory cytokines and chemokines, infiltration of immune cells, and markers of Th2/Th17/Th22 T cell responses. Moreover, serum IgE and Tslp levels were elevated. Our on September 7, 2016 study identifies KLK5 as an important contributor to the NS proteolytic cascade and provides a new and viable model for the evaluation of future targeted therapies for NS or related diseases such as atopic dermatitis.
    [Show full text]
  • Is C. 1431-12G> AA Common European Mutation of Report of A
    19 (2), 2016 l 81-84 DOI: 10.1515/bjmg-2016-0040 CASE REPORT IS c.1431-12G>A A COMMON EUROPEAN MUTATION OF SPINK5? REPORT OF A PATIENT WITH NETHERTON SYNDROME Śmigiel R1,*, Królak-Olejnik B2, Śniegórska D3, Rozensztrauch A1, Szafrańska A2, Sasiadek MM4, Wertheim-Tysarowska K3 *Corresponding Author: Robert Śmigiel, M.D., Ph.D., Department of Pediatrics, Wroclaw Medical University, Bartla 5, PL 51-618 Wroclaw, Poland. Tel: +48-71-784-13-26. Fax: +48-71-784-00-63. E-mail: robert.smigiel@ umed.wroc.pl ABSTRACT decreased capacity to bind water [2]. Recurrent infec- tions, IgG abnormalities, enteropathy, elevated IgE lev- Netherton Syndrome (NS) is a very rare genetic skin els, and hypo-albuminemia are other common features disease resulting from defects in the SPINK5 gene (encod- of the disease [3]. Chronic skin inflammation results ing the protease inhibitor lympho-epithelial Kazal type in scaling and exfoliation, predisposing these patients inhibitor 1, LEKTI1). In this report, we provide a detailed to life-threatening infections, sepsis, hypernatremic de- clinical description of a Polish patient with two SPINK5 hydration or pneumonia. Disease manifestations vary mutations, the novel c.1816_1820+21delinsCT and pos- considerably among NS individuals [4]. Many children sibly recurrent c.1431-12G>A. A detailed pathogenesis suffer from a failure to thrive in the first year of life and of Netherton Syndrome, on the basis of literature review, most of them remain underweight and have short stature. is discussed in the view of current knowledge about the Other reported features include intellectual disability LEKT1 molecular processing and activity.
    [Show full text]
  • KLK5 and KLK7 Ablation Fully Rescues Lethality of Netherton Syndrome-Like Phenotype
    http://www.diva-portal.org This is the published version of a paper published in PLoS Genetics. Citation for the original published paper (version of record): Kasparek, P., Ileninova, Z., Zbodakova, O., Kanchev, I., Benada, O. et al. (2017) KLK5 and KLK7 Ablation Fully Rescues Lethality of Netherton Syndrome-Like Phenotype. PLoS Genetics, 13(1): e1006566 https://doi.org/10.1371/journal.pgen.1006566 Access to the published version may require subscription. N.B. When citing this work, cite the original published paper. Permanent link to this version: http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-132846 RESEARCH ARTICLE KLK5 and KLK7 Ablation Fully Rescues Lethality of Netherton Syndrome-Like Phenotype Petr Kasparek1,2, Zuzana Ileninova1, Olga Zbodakova1, Ivan Kanchev3, Oldrich Benada4, Karel Chalupsky1,3, Maria Brattsand5, Inken M. Beck3, Radislav Sedlacek1,3* 1 Laboratory of Transgenic Models of Diseases, Division BIOCEV, Institute of Molecular Genetics of the Czech Academy of Sciences, v.v.i., Vestec, Czech Republic, 2 Faculty of Sciences, Charles University in Prague, Prague, Czech Republic, 3 Czech Centre for Phenogenomics, Division BIOCEV, Institute of a1111111111 Molecular Genetics of the Czech Academy of Sciences, v.v.i., Vestec, Czech Republic, 4 Laboratory of a1111111111 Molecular Structure Characterization, Institute of Microbiology of the Czech Academy of Sciences, v.v.i., a1111111111 Prague, Czech Republic, 5 Department of Medical Biosciences, Pathology, Umea University, Umea, Sweden a1111111111 a1111111111 * [email protected] Abstract OPEN ACCESS Netherton syndrome (NS) is a severe skin disease caused by the loss of protease inhibitor Citation: Kasparek P, Ileninova Z, Zbodakova O, LEKTI, which leads to the dysregulation of epidermal proteases and severe skin-barrier Kanchev I, Benada O, Chalupsky K, et al.
    [Show full text]
  • SPINK5 Gene Serine Peptidase Inhibitor, Kazal Type 5
    SPINK5 gene serine peptidase inhibitor, Kazal type 5 Normal Function The SPINK5 gene provides instructions for making a protein called LEKT1. LEKT1 is a type of serine peptidase inhibitor. Serine peptidase inhibitors control the activity of enzymes called serine peptidases, which break down other proteins. LEKT1 is found in the skin and in the thymus, which is a gland located behind the breastbone that plays an important role in the immune system by producing white blood cells called lymphocytes. LEKT1 controls the activity of certain serine peptidases in the outer layer of skin (the epidermis), especially the tough outer surface known as the stratum corneum, which provides a sturdy barrier between the body and its environment. Serine peptidase enzymes are involved in normal skin shedding by helping to break the connections between cells of the stratum corneum. LEKT1 is also involved in normal hair growth, the development of lymphocytes in the thymus, and the control of peptidases that trigger immune system function. Health Conditions Related to Genetic Changes Netherton syndrome At least 70 SPINK5 gene mutations have been identified in people with Netherton syndrome, a disorder involving skin and hair abnormalities and a high risk of allergies, asthma, and an inflammatory skin condition called eczema. Mutations in the SPINK5 gene result in a LEKT1 protein that is unable to control serine peptidase activity. The lack of LEKT1 function allows the serine peptidases to be abnormally active and break down too many proteins in the stratum corneum. As a result, excessive skin shedding takes place, and the stratum corneum is unusually thin and breaks down easily, resulting in the skin abnormalities that occur in Netherton syndrome.
    [Show full text]
  • Multifaceted Analyses of Epidermal Serine Protease Activity in Patients with Atopic Dermatitis
    International Journal of Molecular Sciences Article Multifaceted Analyses of Epidermal Serine Protease Activity in Patients with Atopic Dermatitis Hayato Nomura 1, Mutsumi Suganuma 2, Takuya Takeichi 2, Michihiro Kono 3, Yuki Isokane 1, Ko Sunagawa 1, Mina Kobashi 1, Satoru Sugihara 1, Ai Kajita 1, Tomoko Miyake 1, Yoji Hirai 1, Osamu Yamasaki 1, Masashi Akiyama 2 and Shin Morizane 1,* 1 Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan; [email protected] (H.N.); [email protected] (Y.I.); [email protected] (K.S.); [email protected] (M.K.); [email protected] (S.S.); [email protected] (A.K.); [email protected] (T.M.); [email protected] (Y.H.); [email protected] (O.Y.) 2 Department of Dermatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; [email protected] (M.S.); [email protected] (T.T.); [email protected] (M.A.) 3 Department of Dermatology and Plastic Surgery, Akita University Graduate School of Medicine, Hondo 1-1-1, Akita-shi, Akita 010-8543, Japan; [email protected] * Correspondence: [email protected]; Tel.: +81-86-235-7282 Received: 18 December 2019; Accepted: 28 January 2020; Published: 30 January 2020 Abstract: The serine proteases kallikrein-related peptidase (KLK) 5 and KLK7 cleave cell adhesion molecules in the epidermis.
    [Show full text]
  • Domain 15 of the Serine Proteinase Inhibitor LEKTI Blocks HIV Infection in Vitro
    Vol. 22, No. 3, August 2013 LEKTI blocks HIV infection 131 Domain 15 of the serine proteinase inhibitor LEKTI blocks HIV infection in vitro David Palesch,1 Edina Varga,1 Ute C. Marx,2 Klaus Vitzithum,2 Peter Kreutzmann,3 Wolf-Georg Forssmann,4 Jan Münch,1 Hans-Jürgen Mägert5 1 Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany 2 Lehrstuhl Biopolymere, University of Bayreuth, Bayreuth, Germany 3 IPF PharmaCeuticals GmbH, Hannover, Germany 4 Clinic of Immunology and Rheumatology, Peptide Research Group, Hannover Medical School, Hannover, Germany 5 Institute of Biotechnology, Anhalt University of Applied Sciences, Köthen, Germany Abstrak Latar belakang: Inhibitor terkait inhibitor proteinase tipe limfo-epitelial Kazal (LEKTI) adalah inhibitor proteinase serin yang terdiri atas 15-domain, yang bagiannya pertama kali diisolasi dari filtrat darah manusia. LEKTI dikode oleh gen SPINK5. Berbagai penelitian telah melaporkan aktivitas anti-virus pada inhibitor proteinase serin tertentu, seperti inhibitor proteinase mukosa dan inhibitor proteinase alpha1. Penelitian ini bertujuan menguji aktivitas anti-HIV dari dua domain yang mewakili inhibitor proteinase LEKTI. Metode: LEKTI domain 6 dan 15 diproduksi secara rekombinan dalam E. coli. Untuk menguji aktivitas anti-HIV dari kedua domain tersebut, galur sel reporter P4-R5 MAGI yang mengandung gen reporter yang dapat diinduksi oleh HIV, diinfeksi dengan strain HIV CCR5 tropik, dan ditambahkan kedua domain tersebut dalam berbagai konsentrasi. Sesudah tiga hari, laju infeksi ditentukan dengan mengukur aktivitas ß-galaktosidase menggunakan kit Galacto-Light Plus™ untuk uji gen reporter ß-galactosidase. Hasil: LEKTI domain 15 menghambat aktivitas gen reporter terinduksi HIV dengan nilai IC50 sekitar 29 µM, sedangkan domain 6 tidak.
    [Show full text]