A viable mouse model for Netherton syndrome based on mosaic inactivation of the <i>Spink5</i> gene

Kašpárek, Petr; Ileninova, Zuzana; Haneckova, Radka; Kanchev, Ivan; Jenickova, Irena; Sedláček, Radislav

doi:10.1515/hsz-2016-0194

Cited by 12 publications

(11 citation statements)

References 17 publications

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“…Sp5 A135X/A135X mice were born in normal Mendelian ratios, however they exhibited severe skin phenotype with exfoliating epidermis, predominantly localized in the abdominal and facial area ( Fig 1E ) and died within 12 hours after delivery. These phenotypical features mimic NS characteristics and correspond to previously published mouse models of Netherton syndrome [ 15 , 26 – 28 ].…”

Section: Resultssupporting

confidence: 86%

KLK5 and KLK7 Ablation Fully Rescues Lethality of Netherton Syndrome-Like Phenotype

et al. 2017

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Netherton syndrome (NS) is a severe skin disease caused by the loss of protease inhibitor LEKTI, which leads to the dysregulation of epidermal proteases and severe skin-barrier defects. KLK5 was proposed as a major protease in NS pathology, however its inactivation is not sufficient to rescue the lethal phenotype of LEKTI-deficient mice. In this study, we further elucidated the in vivo roles of the epidermal proteases in NS using a set of mouse models individually or simultaneously deficient for KLK5 and KLK7 on the genetic background of a novel NS-mouse model. We show that although the ablation of KLK5 or KLK7 is not sufficient to rescue the lethal effect of LEKTI-deficiency simultaneous deficiency of both KLKs completely rescues the epidermal barrier and the postnatal lethality allowing mice to reach adulthood with fully functional skin and normal hair growth. We report that not only KLK5 but also KLK7 plays an important role in the inflammation and defective differentiation in NS and KLK7 activity is not solely dependent on activation by KLK5. Altogether, these findings show that unregulated activities of KLK5 and KLK7 are responsible for NS development and both proteases should become targets for NS therapy.

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Section: Resultssupporting

confidence: 86%

KLK5 and KLK7 Ablation Fully Rescues Lethality of Netherton Syndrome-Like Phenotype

et al. 2017

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“…NS is caused by loss-of-function mutations in SPINK5 encoding LEKTI protein. LEKTI deficiency results in unopposed protease activity in the epidermis (Chavanas et al, 2000;Descargues et al, 2005;Kasparek et al, 2016). The main targets of LEKTI are the kallikreinrelated peptidases (KLKs), mainly KLK5, KLK7, and KLK14 (Deraison et al, 2007;Egelrud et al, 2005;Hovnanian, 2013;Meyer-Hoffert et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…Spink5 knockout (Spink5KO) mice were the first in vivo model that faithfully reproduced all clinical features of patients with NS, but these animals died from dehydration only a few hours after birth (Descargues et al, 2005;Hewett et al, 2005;Kasparek et al, 2016Kasparek et al, , 2017Yang et al, 2004). Despite neonatal Spink5KO lethality, this model was instrumental in disclosing the involvement of KLKs in NS pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Transgenic Kallikrein 14 Mice Display Major Hair Shaft Defects Associated with Desmoglein 3 and 4 Degradation, Abnormal Epidermal Differentiation, and IL-36 Signature

Gouin

Barbieux

Leturcq

et al. 2020

Journal of Investigative Dermatology

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Netherton syndrome is a rare autosomal recessive skin disease caused by loss-of-function mutations in SPINK5 encoding LEKTI protein that results in unopposed activity of epidermal kallikrein-related peptidases (KLKs), mainly KLK5, KLK7, and KLK14. Although the function of KLK5 and KLK7 has been previously studied, the role of KLK14 in skin homeostasis and its contribution to Netherton syndrome pathogenesis remains unknown. We generated a transgenic murine model overexpressing human KLK14 (TghKLK14) in stratum granulosum. TghKLK14 mice revealed increased proteolytic activity in the granular layers and in hair follicles. Their hair did not grow and displayed major defects with hyperplastic hair follicles when hKLK14 was overexpressed. TghKLK14 mice displayed abnormal epidermal hyperproliferation and differentiation. Ultrastructural analysis revealed cell separation in the hair cortex and increased thickness of Huxley's layer. Desmoglein (Dsg) 2 staining was increased, whereas Dsg3 and Dsg4 were markedly reduced. In vitro studies showed that hKLK14 directly cleaves recombinant human DSG3 and recombinant human DSG4, suggesting that their degradation contributes to hair abnormalities. Their skin showed an inflammatory signature, with enhanced expression of IL-36 family members and their downstream targets involved in innate immunity. This in vivo study identifies KLK14 as an important contributor to hair abnormalities and skin inflammation seen in Netherton syndrome.

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“…Another application took advantage of CRISPR-Cas9 mediated multiple genes editing, hence got one-step strategy for generating different kinds of immunodeficient mouse models [73]. In virtue of engineered nucleases mediated genome modifications, there have been other animal disease models for simulating Hermansky Pudlaksyndrome [74], human smallpox [75], Laron syndrome [76], colitis [77], Netherton syndrome [78] and so on. The advancements in genome editing technologies will further expand the use of animal models in biomedicine and beyond.…”

Section: Genome Editing For Disease Modelingmentioning

confidence: 99%

Applications of Genome Editing Technology in Animal Disease Modeling and Gene Therapy

Zhou

Wang

et al. 2019

Computational and Structural Biotechnology Journal

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Genome editing technology is a technique for targeted genetic modifications, enabling the knockout and addition of specific DNA fragments. This technology has been widely used in various types of biomedical research, clinics and agriculture. In terms of disease research, constructing appropriate animal models is necessary. Combining reproductive technology with genome editing, many animal disease models have been generated for basic and clinical research. In addition, precisely targeted modifications allow genome editing to flourish in the field of gene therapy. Many mutations refractory to traditional gene therapy could be permanently corrected at the DNA level. Thus, genome editing is undoubtedly a promising technology for gene therapy. In this review, we mainly introduce the applications of genome editing in constructing animal disease models and gene therapies, as well as its future prospects and challenges.

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A viable mouse model for Netherton syndrome based on mosaic inactivation of the Spink5 gene

Cited by 12 publications

References 17 publications

KLK5 and KLK7 Ablation Fully Rescues Lethality of Netherton Syndrome-Like Phenotype

KLK5 and KLK7 Ablation Fully Rescues Lethality of Netherton Syndrome-Like Phenotype

Transgenic Kallikrein 14 Mice Display Major Hair Shaft Defects Associated with Desmoglein 3 and 4 Degradation, Abnormal Epidermal Differentiation, and IL-36 Signature

Applications of Genome Editing Technology in Animal Disease Modeling and Gene Therapy

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