DOCSLIB.ORG

SPINK5 and Netherton Syndrome: Novel Mutations, Demonstration of Missing LEKTI, and Differential Expression of Transglutaminases

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
SPINK5 and Netherton Syndrome: Novel Mutations, Demonstration of Missing LEKTI, and Differential Expression of Transglutaminases SPINK5 and Netherton Syndrome: Novel Mutations, Demonstration of Missing LEKTI, and Differential Expression of Transglutaminases Michael Raghunath,Ãz1 Lambrini Tontsidou,w1 Vinzenz Oji,Ã1 Karin Aufenvenne,à Funda Schu¨ rmeyer-Horst,à Arumugam Jayakumar,z Hartmut Sta¨ nder,à Josef Smolle,y Gary L. Claymanz and Heiko Traupeà ÃDepartment of Dermatology and wInstitute of Human Genetics, University Hospital, Mu¨ nster, Germany; zDepartment of Head and Neck Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA; yDepartment of Dermatology, University Hospital Graz, Austria; zDivision of Bioengineering and Department of Biochemistry, National University of Singapore, Singapore Netherton syndrome (NTS) is an autosomal recessive congenital ichthyosis featuring chronic inflammation of the skin, hair anomalies, epidermal hyperplasia with an impaired epidermal barrier function, failure to thrive and atopic manifestations. The disease is caused by mutations in the SPINK5 gene encoding the serine proteinase inhibitor lympho-epithelial Kazal-type inhibitor (LEKTI). Sequence analyses of SPINK5 in seven NTS patients from five different families allowed us to identify two known and three novel mutations all creating premature termination codons. We developed a monoclonal antibody giving a strong signal for LEKTI in the stratum granulosum of normal skin and demonstrated absence of the protein in NTS epidermis. Immunoblot analysis revealed presence of full length LEKTI and of LEKTI cleavage fragments in normal hair roots, whereas in NTS hair roots LEKTI and its cleavage products were completely missing. Transglutaminase1 activity was present throughout almost the entire suprabasal epidermis in NTS, whereas in normal skin it is restricted to the stratum granulosum. In contrast, immunostaining for transglutaminase3 was absent or faint. Moreover, comparable with the altered pattern in psoriatic skin the epidermis in NTS strongly expressed the serine proteinase inhibitor SKALP/elafin and the anti- microbial protein human b-defensin 2. These studies demonstrate LEKTI deficiency in the epidermis and in hair roots at the protein level and an aberrant expression of other proteins, especially transglutaminase1 and 3, which may account for the impaired epidermal barrier in NTS. Key words: elafin/epidermal barrier/genetics/human b-defensin 2/mutation/Netherton syndrome/serine protei- nases/skin/transglutaminase J Invest Dermatol 123:474 –483, 2004 Netherton syndrome (NTS), a rare autosomal recessive Because of the variable expression of skin signs and genodermatosis, combines chronic and severe inflamma- delayed onset of characteristic hair abnormalities the tion of the skin with hair shaft anomalies and atopic diagnosis of NTS is often delayed. Frequently, the con- features. The degree of skin involvement varies, some comitant atopic diathesis with elevated IgE levels, asthma, patients show severe congenital ichthyosiform erythroder- and hay fever leads to misdiagnosis of severe atopic ma (CIE), whereas most present with ichthyosis linearis dermatitis (AD). Other cases are initially misclassified as circumflexa (ILC)––polycyclic migrating plaques with char- Leiner disease––severe seborrhoic generalized dermatitis acteristic double-edged scales (Traupe, 1989). Often pa- (Hausser and Anton-Lamprecht, 1996). Histopathology tients display at birth CIE, which in some of them improves does not allow to distinguish NTS from disorders such as and evolves into ILC. The finding of trichorrhexis invaginata psoriasis, because both conditions display focal para- (‘‘Bamboo hairs’’) is diagnostic (Sybert, 1997). These and keratosis with psoriasiform epidermal hyperplasia, focal other hair anomalies (pili torti, trichorrhexis nodosa), absence of the granular layer, intraepidermal neutrophil however, are not always present and even repeated hair accumulation and at the functional level an impaired samples may be negative. Other conditions often asso- epidermal barrier (Hausser and Anton-Lamprecht, 1996). ciated with NTS are delayed growth, recurrent infections, The list of differential diagnoses also includes erythrodermic urticaria, angioedema, failure to thrive, aminoaciduria, and psoriasis, erythrokeratoderma variabilis, and acrodermatitis in some instances slight mental retardation (Greene and enteropathica because of the perioral and perianal accent- Muller, 1985). uation of erythema and scaling (Greene and Muller, 1985). Recently, the diagnosis of NTS by molecular genetic analysis became possible due to the mapping of the Abbreviations: AD, atopic dermatitis; hBD-2, human b-defensin 2; respective gene locus on chromosome 5q32 (Chavanas LEKTI, lympho-epithelial Kazal-type inhibitor; NTS, Netherton syndrome; PTC, premature termination codon et al, 2000a) and subsequent identification of mutations in 1Authors have contributed equally. the SPINK5 gene (Chavanas et al, 2000a, b; Sprecher et al, Copyright r 2004 by The Society for Investigative Dermatology, Inc. 474 hBD-2 and elafin inand NTS. we observedNTS, which the may unexpectedlyably explain discordant strong expression the of presencedeficiency. disturbed transglutaminases1 In of epidermal and addition, 3 we barrier, mutations, in found a differential all andelafin. Here, remark- of we report two them known and resulting three novel in epidermal LEKTI microbial peptides human severe infections weepidermal analyzed the differentiation. expression Incross-linking of view the of of anti- behavior the the of susceptibility transglutaminasesand cornified to which in play envelopewe view a wondered and key of howpatients role LEKTI thus the on for mutations the expression for epidermal disturb of keratinization epidermal hyperplasia LEKTI. In studied addition, the body to assessremains the unclear. effects Weother of developed a tissue, novelin but monoclonal epidermis, pilosebaceous anti- its units (Komatsu domains precise remains to be biological determined.assignment LEKTI function mRNA is of present specific inhibitory activity to individual (Ma plasmin, trypsin, subtilisinLEKTI inhibits A, cathepsin G, and elastase predict a significant truncationnot of found the in LEKTI polypeptide. 80transmitted normal by chromosomes. both All (non-consanguineous)Bosnia). novel parents. mutations In It was two the independent patients of family differentwas ethnic origins from found (Austria, in Bosniaacceptor the splice heterozygous this site used andacceptor for mutation homozygous splice exon state 16 site was (Fig in 10cagtttcttaaagTCAA. 2). This bp This predicts upstream mutation an ofcggtttcttaaagTCAA additional the (splice very site wild-type strong underlined) aAG services/NetGene2/) was changed showed to thatfruitfly.org/seq_tools/splice.html and the http://www.cbs.dtu.dk/ wild-type sequence Prediction ProgrammA by detailed analysisaffects Neural of intron 15 this Network near mutation theand intron–exon using (http://www. 3.2 boundary the to by exonmutation Splice their 16. in Site father. family The398delTG H novel in was mutation transmitted exon 1432–13codon to G>A 5 both immediately (PTC) patients resultsleads 3.1 into to after a a frameshift PTC.mutation six resulting (Fig This into 2). Patient a codons. 1 prematuresiblings is termination homozygous for The 2.1/2.2, 715insT, which recurrent who two-bp acceptor are splice deletion bp homozygous site deletion for mutation inThe family in this novel mutations H patient putative are (patient an 5,revealed insertion 3.1 three of and T novel and in and 3.2; patientMutation two 1, analyses Fig published a two- mutations 1) (Table and I). a hibitory domains (Ma cysteine-rich protein consistingepithelial of Kazal-type 15encodes inhibitor) Kazal-type-like a serine in- (Ma protease2001; Komatsu inhibitor called LEKTI (lympho- 123 : 3 SEPTEMBER 2004 ¨ gert et al , 2002b; Mitsudo in vitro et al ¨ , 2002; Bitoun Mutation analysis by direct sequencing gert a battery of serine proteases including Results et al b -defensin 2 (hBD-2) and SKALP/ , 2002a). Recombinant human et al SPINK5 et al ¨ , 2003), but the exact gert , 2002a, b). mutations in NTS et al et al , 1999), a , 2002) and SPINK5 SPINK5 in vivo Table I. Netherton syndrome, mutations in SPINK5 LEKTI DEFICIENCY IN NETHERTON SYNDROME Patient Mutations Location Nucleotide change Predicted consequence Mutation published 1a 715insT homozyg. Exon 9 within domain 4 C(T)6G ! C(T)7G Frameshift (PTC þ 6) Novel 2.1 1432-13 G4A homozyg. Exon 16 after domain 7 cggtttcttaaagTCAA ! cagtttcttaaagTCAA putative splice site upstream Novel 2.2 1432-13 G4A homozyg. Exon 16 after domain 7 cggtttcttaaagTCAA ! cagtttcttaaagTCAA putative splice site upstream Novel 3.1 398delTG Exon 5 within domain 2 TGTGCT ! TGCTGA Frameshift (PTC þ 1) Novel R790X Exon 25 within domain 12 ACTCGA ! ACTTGA 2368 PTC Chavanas et al (2000b) 3.2 398delTG Exon 5 within domain 2 TGTGCT ! TGCTGA (PTC þ 1) Novel R790X Exon 25 with domain 12 ACTCGA ! ACTTGA 2368 PTC Chavanas et al (2000b) 4a 2468insA homozyg. exon 26 end of domain 12 G(A)10G ! G(A)11G Frameshift (PTC þ 4) Chavanas et al, 2000b 5 1432-13 G>A Exon 16 after domain 7 cggtttcttaaagTCAA ! cagtttcttaaagTCAA putative splice site upstream Novel 2468insA Exon 26 end of domain 12 T(A)10G ! T(A)11G Frameshift (PTC þ 4) Chavanas et al (2000b) aconsanguineous parents: first cousins 475 476 RAGHUNATH ET AL THE JOURNAL OF INVESTIGATIVE DERMATOLOGY healthy individuals (n ¼ 5) visualizing the full length protein at 140 kDa. At least three further LEKTI fragments could be seen at approximately 110, 90, and 60
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]
  • 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.
    [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]