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Consequences of keratin mislocalization using ichthyosis with confetti (IWC) as a model disease

English title Consequences of keratin mislocalization using ichthyosis with confetti (IWC) as a model disease
Applicant Burger Bettina
Number 188837
Funding scheme Project funding (Div. I-III)
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Immunology, Immunopathology
Start/End 01.04.2020 - 31.03.2024
Approved amount 302'150.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Experimental Cancer Research

Keywords (9)

natural gene therapy; chromosomal rearrangement; keratin; Ichthyosis with confetti; LOH; skin inflammation; non-melanoma skin cancer; nuclear localization; model disease

Lay Summary (German)

Lead
Angeborene Erkrankungen ermöglichen der Forschung, die üblichen Abläufe in einem Organismus besser zu verstehen. Bei der Ichthyosis with confetti (IWC), einer angeborene Hauterkrankung, findet eine Form von Selbstheilung in einigen Bereichen der Haut statt. Das Projekt möchte diese Selbstheilung besser verstehen, um ihre gezielte Anwendung für Therapien zu ermöglichen.
Lay summary

Personen, die eine IWC haben, haben von Geburt an eine sehr trockene gerötete Haut. Alle Patienten bekommen im Laufe ihres Lebens auf dieser geröteten Haut Flecken unterschiedlicher Grösse, die wie gesunde Haut aussehen. Allen Patienten gemeinsam ist eine Veränderung in dem Gen für Keratin (KRT) 10 oder KRT1. Die Eiweisse KRT10/KRT1 werden in Zellen der oberen Haut (Keratinozyten) gebildet und sind im Zellplasma angeordnet. Bei IWC-Patienten wird das KRT10/KRT1 vom Zellplasma in den Zellkern transportiert. Im Zellkern führt es auf unbekannte Weise zur «Reparatur» der Veränderung auf dem KRT10/KRT1-Gen. In den Bereichen, wo dies geschieht, entstehen die Flecken gesund aussehender Haut. Wir untersuchen den Transport des Keratins in den Zellkern und die «Reparatur» der Veränderung. Wir untersuchen auch, warum diese «Reparatur» nicht in allen Keratinozyten stattfindet und ob noch weitere Zelltypen und Organe davon betroffen sind. Wenn wir diese Reparaturmechanismen besser verstehen, können wir sie möglicherweise für die Therapie bei der IWC aber auch bei anderen Erkrankungen einsetzen.

Das Projekt befasst sich mit medizinischer Grundlagenforschung. Um Hauterkrankungen besser behandeln zu können ist es wichtig, die gegenseitigen Beziehungen der Eiweisse in der Haut zu verstehen. Dies ermöglicht uns die Untersuchung der Abläufe in IWC-Keratinozyten.

Direct link to Lay Summary Last update: 04.03.2020

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Abstract

Ichthyosis with confetti (IWC) is an autosomal dominant hereditary disorder that shows intriguing phenomena with the potential to explain general mechanisms in human skin. Patients with this inborn disease suffer lifelong from erythroderma (erythema and scaling skin). Subsequently however, all patients start to develop pale spots of different dimension within the inflamed skin area, which look like healthy skin. All patients are carrier of a heterozygous variant in either the keratin (KRT) 10 or KRT1 gene. These variants are insertions or deletions of some nucleotides resulting in a shifted reading frame (frameshift) and translation of an aberrant carboxy (C)-terminus. 54 distinct keratins (KRT) are known. They are intermediate filaments, which are responsible for mechanical cell stability in human epidermis. Within the cells of the epidermis (keratinocytes) KRT are localized in the cytoplasm. They heterodimerize and subsequently heteropolymerize to form intermediate filaments. In erythrodermic epidermis of IWC patients however, the mutant KRT and its assembly partner are aberrantly localized in the nucleus. The underlying nuclear import system is unknown. Once the phenotype reverts to a pale spot all local KRT are again correctly localized in the cytoplasm. DNA analyses of the pale spots revealed a loss of the mutant allele and its replacement by a second copy of the wildtype allele, so that the affected keratinocytes display a loss of heterozygosity (LOH). The underlying pathomechanism is not yet understood. Hence, the local, specific LOH allows the skin to revert to the normal phenotype. This mechanism could potentially be highly useful for treatment of other dominant skin conditions. The nuclear localization of aberrant KRT is probably the cause of the inflammation, as other keratins have been shown to be key switches of inflammation once localized in the nucleus. In addition, the type of inflammation produced by the pathologic KRT1/10 variants remains to be characterized on the cytokine and intra-cellular signalling level. We intend to explain the pathomechanism of IWC addressing questions regarding interactions of the aberrant KRT with other proteins and chromatin as well as its effects on epidermal and non-epidermal cells. We will achieve five aims by testing several hypotheses in vitro and in vivo. In aim 1 we focus on understanding the natural restriction of spot size and the development of new spots. In aim 2 we plan to identify a possible occurrence of chromosomal rearrangements apart from epidermis. In aim 3 we attempt to understand the influence of the pathological KRT on chromosomal rearrangements whereas in aim 4 we plan to discover the mechanism that is used by aberrant KRT for nuclear import. In aim 5 we seek for overlaps and discrepancies between IWC-correlated and sporadic skin cancer. Ultra-deep next-generation sequencing (UD-NGS) as well as methods that increase the specificity and sensitivity in detection of a protein on its particular localization will be used to understand development and size of a pale spot. Transcriptomics of biopsies and model systems will potentially reveal specific expression patterns of erythrodermic skin and pale spots. Data will be linked to transcriptome analyses in skin cancer of IWC patients and the general population. Chromosomal rearrangements in mesodermal germ layers without KRT expression will be examined, elucidating consequences of the pathogenic KRT-variant on tissue apart from ectodermal epidermis. SNP arrays will be used for detection of expected genome-wide LOH in IWC patients’ epidermis and maybe further tissues. Finally, the type of nuclear import shuttle relevant in keratinocytes for KRT nuclear import will be investigated. Understanding the IWC-pathomechanism means increasing the knowledge about general intra- and intercellular signalling, skin inflammation and proliferation, as well as chromosomal rearrangements and LOH. Our project is the first study that systematically examine the IWC pathomechanism. It therefore may allow the natural gene therapy access to therapeutic applications in other diseases.
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