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Human Molecular Genetics Advance Access published online on December 8, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddi030
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Human Molecular Genetics, Vol. 14, No. 2 © Oxford University Press 2005; all rights reserved

Article

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

Duncan R. Hewett 1*, Alison L. Simons 1, Niamh E. Mangan 2, Helen E. Jolin 1, Shelia M. Green 1, Padraic G. Fallon 2, and Andrew N.J. McKenzie 1

1 MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 2QH, United Kingdom
2 Department of Biochemistry, Trinity College, Dublin 2, Ireland

* To whom correspondence should be addressed.
Duncan R. Hewett, E-mail: drhewett{at}mrc-lmb.cam.ac.uk


  Abstract

Netherton syndrome is an autosomal recessive multisystemic disorder characterised 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 spink5R820X/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 due to 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 wildtype and spink5R820X/R820X mice revealed a substantial increase in the proteolytic processing of profilaggrin into its constituent filaggrin monomers. Filaggrin functions to organise keratin filaments into highly ordered macrofibrils that criss-cross 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.


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