Lethal, neonatal ichthyosis with increased proteolytic processing of filaggrin in a mouse model of Netherton syndrome

Abstract

Netherton syndrome is an autosomal recessive multisystemic disorder characterized by congenital ichthyosiform erythroderma, hair shaft defects and atopy, caused by mutations within the human SPINK5 gene. To investigate the development of this disease, we have cloned mouse spink5 and created mice with a mutated premature stop codon at amino acid R820X, to produce an allele that closely mimics a point mutation (E827X) in human SPINK5. Newborn spink5(R820X/R820X) mice develop a lethal, severe ichthyosis with a loss of skin barrier function and dehydration, resulting in death within a few hours of birth, similar to that observed in patients with severe Netherton syndrome. Epidermal barrier function is compromised because of the stratum corneum becoming spontaneously detached in the newborn mice, and this is probably compounded by the reduced mechanical strength detected in the cornified envelopes. Biochemical analysis of skin from newborn wild-type and spink5(R820X/R820X) mice revealed a substantial increase in the proteolytic processing of profilaggrin into its constituent filaggrin monomers. Filaggrin functions to organize keratin filaments into highly ordered macrofibrils that crisscross the cornified cells of the stratum corneum imparting structural integrity, and defects in filaggrin processing occur in a number of forms of congenital ichthyosis. These data suggest that in the absence of the serine protease inhibitor spink5, there is an abnormal increase in the processing of profilaggrin, resulting in an overabundance of filaggrin monomers, and that this may play a direct role in the observed deficit in the adhesion of the stratum corneum and the severely compromised epidermal barrier function.

Transgenic kallikrein 5 mice reproduce major cutaneous and systemic hallmarks of Netherton syndrome

“…The development of Spink5 deficient mice provided the first opportunity to unravel the complex pathophysiology of NS in an in vivo experimental model (Yang et al, 2004;Descargues et al, 2005;Hewett et al, 2005;Briot et al, 2009). Spink5 / animals display a phenotype highly reminiscent of NS, replicating cutaneous and inflammatory aspects of the disease.…”

“…Despite the neonatal lethality of Spink5 deficient mice (Yang et al, 2004;Descargues et al, 2005;Hewett et al, 2005), considerable progress has been made on detailing the biologi cal pathways involved in NS pathophysiology. However, the significance of each protease implicated in the disease remains unclear.…”

“…The experiment was performed three times. display key features of NS but die shortly after birth (Yang et al, 2004;Descargues et al, 2005;Hewett et al, 2005). Here, we developed a new model of NS by overexpressing KLK5 in the epidermis.…”

“…Synthesized as a large (145 kD) polypro tein containing 15 Kazal domains, LEKTI is cleaved by furin to liberate a series of smaller fragments comprising one or more inhibitory units that target distinct protease subsets (Bitoun et al, 2003;Fortugno et al, 2011). LEKTI of rapid dehydration (Yang et al, 2004;Descargues et al, 2005;Hewett et al, 2005).…”

Cervical remodeling during pregnancy and parturition: molecular characterization of the softening phase in mice

“…K/K mice die a few hours after birth from dehydration due to the lack of an intact permeability barrier of skin (Hewett et al 2005). The gene product, lymphoepithelial Kazal-type related inhibitor, is a serine protease inhibitor that attenuates the functions of stratum corneum tryptic enzymes, which degrade desmoglein 1 as well as other proteins involved in barrier formation and maintenance (Descargues et al 2005).…”