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Human Molecular Genetics Advance Access published online on June 9, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh178
© 2004 by Oxford University Press
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Article

Transgenic mouse models support HCR as an effector gene in the PSORS1 locus

Outi Elomaa 1, Inkeri Majuri 1, Sari Suomela 2, Kati Asumalahti 3, Hong Jiao 4, Zahra Mirzaei 4, Bjorn Rozell 5, Karin Dahlman-Wright 4, Johanna Pispa 6, Juha Kere 7*, Ulpu Saarialho-Kere 8

1 Departments of Medical Genetics, University of Helsinki, and Helsinki University Central Hospital, Helsinki, Finland
2 Departments of Dermatology, University of Helsinki, and Helsinki University Central Hospital, Helsinki, Finland
3 Departments of Medical Genetics, University of Helsinki, and Helsinki University Central Hospital, Helsinki, Finland; Departments of Dermatology, University of Helsinki, and Helsinki University Central Hospital, Helsinki, Finland
4 Department of Biosciences at Novum, Huddinge University Hospital, Huddinge, Sweden
5 Division of Clinical Research Center and Pathology, Department of Laboratory Medicine, Huddinge University Hospital, Huddinge, Sweden
6 Institute of Biotechnology, University of Helsinki, and Helsinki University Central Hospital, Helsinki, Finland
7 Departments of Medical Genetics, University of Helsinki, and Helsinki University Central Hospital, Helsinki, Finland; Department of Biosciences at Novum, Karolinska Institutet, Huddinge University Hospital, 14157 Huddinge, Sweden; Division of Clinical Research Center and Pathology, Department of Laboratory Medicine, Huddinge University Hospital, Huddinge, Sweden
8 Departments of Dermatology, University of Helsinki, and Helsinki University Central Hospital, Helsinki, Finland; Karolinska Institutet at Stockholm Soder Hospital, Stockholm, Sweden

* To whom correspondence should be addressed. E-mail: juha.kere{at}biosci.ki.se.


  Abstract

Genetic susceptibility for psoriasis is regulated to the greatest extent by the PSORS1 locus. Three psoriasis associated susceptibility alleles have been identified within it, namely HLACw6, HCR*WWCC and CDSN*5, but strong linkage disequilibrium between them has made it difficult to distinguish their individual genetic effects, and animal models to study their effects are not known. In order to study the function of HCR, we engineered transgenic mice with either a nonrisk allele of HCR or the HCR*WWCC risk allele under the control of the cytokeratin-14 promoter. These choices were motivated by the apparently dominant effect of PSORS1 on psoriasis susceptibility and the physiological expression of HCR in basal keratinocytes. Transgenic mice appeared phenotypically normal, and histologically their skin was indistinguishable from wild-type mice. Expression studies using Affymetrix arrays suggested that the HCR risk allele has specific functional consequences relevant to the pathogenesis of psoriasis. Comparison of gene expression changes between nonrisk and risk allele mice revealed similarities to previous observations in human psoriatic skin, including upregulation of cytokeratins 6, 16 and 17 in risk allele mice. We also observed changes in the expression of genes associated with terminal differentiation and formation of the cornified cell envelope. Our results support the concept that HCR may constitute an essential gene in the PSORS1 locus. These observations are also compatible with a model that a susceptibility gene for psoriasis induces changes that are contributory but not sufficient alone to produce the clinical phenotype.


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