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Ichthyin/NIPAL4 localizes to keratins and desmosomes in epidermis and Ichthyin mutations affect epidermal lipid metabolism

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Abstract

Autosomal recessive congenital ichthyosis (ARCI) is a group of disorders characterized by abnormal desquamation of the skin and a disrupted epidermal water barrier. Ichthyin/NIPAL4 gene mutations have been identified in a subgroup of ARCI patients, but the role of ichthyin in epidermis remains elusive. In order to obtain new insights concerning the characteristics of ichthyin and the ARCI pathogenesis, we studied the expression and localization of ichthyin and related epidermal components in cultured keratinocytes and skin sections from patients with Ichthyin mutations and healthy controls. We observed an up-regulation of Ichthyin mRNA levels after in vitro differentiation of keratinocytes from both a patient with Ichthyin mutations and controls. Confocal and electron microscopy analyses of immunolabeled skin sections revealed that ichthyin localizes to desmosomes and keratins in both patients with mutant Ichthyin and controls, with an increased immunolabeling in patients. Nile red lipid analysis of skin sections exposed intra-cellular lipid accumulations in cells of the granular and cornified layers in patients but not in controls, consistent with the pathognomonic lipid membrane structures previously identified in epidermis from patients. Our combined findings indicate that ichthyin is associated with keratins and desmosomes in epidermis and is involved in lipid metabolism, possibly through processing of lamellar bodies. These results provide new clues to the understanding of the epidermal water barrier and the pathogenesis in ARCI.

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Acknowledgments

We thank Dr Hans Törmä and Dr Casimiro Castillejo-Lopez for fruitful discussions and for providing antibodies and Dr Ingrid Hausser for valuable comments. We acknowledge Inger Pihl-Lundin for immunohistochemical work and Hao Li for technical support. This work was supported by the Swedish Research Council (K2010-66X-10829-17-3 to N.D. and K2010-55X-20326-04-03 to G.T.W.), Uppsala University, Science for Life Laboratory and Uppsala University Hospital.

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Authors and Affiliations

  1. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, 75185, Uppsala, Sweden

    Johanna Dahlqvist & Niklas Dahl

  2. Department of Medical Cell Biology, Uppsala University, 75123, Uppsala, Sweden

    Gunilla T. Westermark

  3. Department of Medical Sciences, Uppsala University Hospital, 75185, Uppsala, Sweden

    Anders Vahlquist

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  1. Johanna Dahlqvist
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Correspondence to Niklas Dahl.

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Dahlqvist, J., Westermark, G.T., Vahlquist, A. et al. Ichthyin/NIPAL4 localizes to keratins and desmosomes in epidermis and Ichthyin mutations affect epidermal lipid metabolism. Arch Dermatol Res 304, 377–386 (2012). https://doi.org/10.1007/s00403-012-1207-7

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