Genetic analysis of a severe case of Netherton syndrome and application for prenatal testing

Fb, Müller; Haußer, Ingrid; Berg, Daniel J.; Casper, Claus; Maiwald, R; Jung, Anna; Jung, Hun; Bp, Korge

doi:10.1046/j.1365-2133.2002.04625.x

Cited by 54 publications

(39 citation statements)

References 13 publications

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“…3B). These results are reminiscent of clinical observations in neonatal patients with severe NS, where skin lesions occur preferentially in articular regions and aggravate soon after birth with generalized exfoliative erythroderma (Komatsu et al 2002;Muller et al 2002).…”

Section: Resultssupporting

confidence: 55%

“…Specifically, we observed loosely interconnected corneocytes that contained abnormal low electron-dense vesicles in their cytoplasm (Fig. 4F), a phenomenon observed in human NS samples as well (Muller et al 2002). Furthermore, we found a distinctive architectural loss of cell-cell adhesion (acantholysis) in the granular layer of mutant epidermis (Fig.…”

Section: Resultsmentioning

confidence: 56%

See 1 more Smart Citation

Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5^-/- mice

Yang

Liang²,

Koch³

et al. 2004

Genes Dev.

103

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Netherton syndrome (NS) is a human autosomal recessive skin disease caused by mutations in the SPINK5 gene, which encodes the putative proteinase inhibitor LEKTI. We have generated a transgenic mouse line with an insertional mutation that inactivated the mouse SPINK5 ortholog. Mutant mice exhibit fragile stratum corneum and perinatal death due to dehydration. Our analysis suggests that the phenotype is a consequence of desmosomal fragility associated with premature proteolysis of corneodesmosin, an extracellular desmosomal component. Our mouse mutant provides a model system for molecular studies of desmosomal stability and keratinocyte adhesion, and for designing therapeutic strategies to treat NS.Supplemental material is available at http://www.genesdev.org.Received June 17, 2004; revised version accepted August 6, 2004. Netherton Syndrome (NS) (MIM 256500) is a severe, recessively inherited skin disease in humans with high neonatal lethality. It is characterized by ichthyosiform erythroderma, atopic dermatitis, bamboo hair, skin barrier defects, and elevated IgE levels in survivors (Krafchik and Toole 1983;Judge et al. 1994). Mutations have been identified in the SPINK5 (serine proteinase inhibitor Kazal type 5) gene of NS patients (Chavanas et al. 2000;Sprecher et al. 2001;Walley et al. 2001;Bitoun et al. 2002;Komatsu et al. 2002). SPINK5 encodes LEKTI (lympho-epithelial Kazal-type-related inhibitor), which is a putative proteinase inhibitor that contains an N-terminal signal peptide and 15 domains with high internal homology (Magert et al. 1999). Each domain has four conserved cysteines. Domains 2 and 15 possess two additional cysteines, which make them typical Kazal-type proteinase inhibitor domains (Magert et al. 1999). LEKTI exhibits proteinase inhibitor activity in vitro (Magert et al. 1999;Komatsu et al. 2002;Walden et al. 2002;Mitsudo et al. 2003). In NS patients, loss or reduction of LEKTI activity is presumed to result in elevated proteolytic activity in the suprabasal epidermis, leading to erythroderma and skin-barrier defects. However, the specific proteins that are targeted for degradation in these patients have not been identified. We describe here a Spink5 mutant mouse line that shows severe skin defects associated with desmosomal fragility, and thus, provides insights into the molecular pathogenesis of NS and a novel model system for studies of keratinocyte adhesion. Results and DiscussionTransgenic mouse line OVE1498 was generated by coinjection of a tyrosinase-tagged (Yokoyama et al. 1990) Sleeping Beauty transposon (Ivics et al. 1997) (termed pT-Tybs-3ЈE) along with PGK2-SB10 (Ivics et al. 1997) (see Supplementary Fig. S1) into inbred FVB/N embryos. The transgenic founder and its transgenic F1 offspring were phenotypically normal and showed no evidence for transposition of the transgene(s) (data not shown). When transgenic F1 mice were intercrossed, ∼25% of the newborn offspring developed severe skin blistering and water barrier defects, leading to death within several hours after birth ...

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Section: Resultssupporting

confidence: 55%

Section: Resultsmentioning

confidence: 56%

Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5^-/- mice

Yang

Liang²,

Koch³

et al. 2004

Genes Dev.

103

View full text Add to dashboard Cite

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“…189 In summary, molecular diagnosis is a crucial diagnostic tool and has become in some countries the gold standard for the diagnosis of the ichthyoses and MEDOC in general. It provides a firm basis for genetic counseling of affected individuals and families and permits DNA-based prenatal diagnosis for families at risk, as has been demonstrated in NS, [190][191][192] KPI,[193][194][195] Sjögren-Larsson syndrome, 196 HI, 197,198 and others.…”

Section: Diagnostic Aspects Molecular Geneticsmentioning

confidence: 98%

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009

Oji

Tadini

Akiyama

et al. 2010

Journal of the American Academy of Dermatology

689

704

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“…Loss of function of SPINK5 causes Netherton syndrome, a severe autosomal recessive ichthyosis characterized by chronic dermatitis, asthma, and allergic rhinitis (89). Ultrastructural analyses show a marked increase in corneodesmosome cleavage and SC detachment at the border between transient cells and SG cells in the skin of patients with Netherton syndrome (90)(91)(92). Studies of SPINK5-knockout mice confirmed that LEKTI deficiency results in elevated KLK5 activity in the layers of the SC and subsequent breakdown of corneodesmosin, followed by SC barrier loss (93)(94)(95).…”

Section: Figurementioning

confidence: 99%

Epidermal barrier dysfunction and cutaneous sensitization in atopic diseases

Kubo¹,

Nagao²,

Amagai³

2012

J. Clin. Invest.

322

289

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Classic atopic dermatitis is complicated by asthma, allergic rhinitis, and food allergies, cumulatively referred to as atopic diseases. Recent discoveries of mutations in the filaggrin gene as predisposing factors for atopic diseases have refocused investigators' attention on epidermal barrier dysfunction as a causative mechanism. The skin's barrier function has three elements: the stratum corneum (air-liquid barrier), tight junctions (liquid-liquid barrier), and the Langerhans cell network (immunological barrier). Clarification of the molecular events underpinning epidermal barrier function and dysfunction should lead to a better understanding of the pathophysiological mechanisms of atopic diseases. IntroductionAtopic dermatitis (AD) is a chronic relapsing eczematous skin disorder that is frequently associated with elevated serum IgE levels and a family history of AD, allergic rhinitis, and/or asthma. Clinical manifestations of classic AD are dry skin and relapsing eczema, which usually start during early infancy or childhood and become complicated by food allergies, asthma, and/or allergic rhinitis during the first several years of life, in a process called "atopic march" (1). AD is highly prevalent in industrialized countries, where it affects approximately 15%-30% of children and 2%-10% of adults (2). The various observations of the disease indicate that AD has a complex etiology with genetic, immunological, and environmental aspects.Living organisms rely critically on surface barriers to isolate themselves from the external environment and to maintain homeostasis. While unicellular organisms are enclosed by cell membranes and cell walls, epithelial barrier structures, in several forms, cover the surfaces of multicellular organisms (3). In mammals, the airway and gastrointestinal tract are lined by simple epithelia covered with mucus. In contrast, the outer surface of the body is covered by a stratified epithelial cellular sheet called the epidermis, the outermost layer of which is cornified. Recent findings have shown that disruption of epithelial barrier systems are involved in the pathogenesis of immune disorders such as inflammatory bowel disease, asthma, and AD (4-12). In this review, we describe the barrier system of the epidermis, which is far more sophisticated than previously thought (13,14), and attempt to discuss its function with special focus on antigen penetration through these barriers and antigen capture by dendritic cells in the context of AD.

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Genetic analysis of a severe case of Netherton syndrome and application for prenatal testing

Cited by 54 publications

References 13 publications

Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5^-/- mice

Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5^-/- mice

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009

Epidermal barrier dysfunction and cutaneous sensitization in atopic diseases

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Genetic analysis of a severe case of Netherton syndrome and application for prenatal testing

Cited by 54 publications

References 13 publications

Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5-/- mice

Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5-/- mice

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009

Epidermal barrier dysfunction and cutaneous sensitization in atopic diseases

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Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5^-/- mice

Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5^-/- mice