Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

In situ expression of the mouse dyskeratosis congenital gene, Dkc1: Towards understanding gene function and disease progression

NS Heiss PhD 1, D Bächner PhD 2, A Kolb MSc 1, R Salowsky MSc 1, A Poustka PhD 1

1 German Cancer Research Institute, DKFZ Dept Molecular Genome Analysis, Heidelberg, Germany, 2 University Clinic Eppendorf, Dept Cell Biochemistry and Clinical Neurobiology, Hamburg, Germany,

INTRODUCTION: X-linked dyskeratosis conjoint (DKC) is a progressive multisystem disorder most severely affecting tissues with a high cellular turnover such as skin and blood. Most patients die of bone marrow failure, although the chances of developing various types of cancer are also high. Predominantly missense mutations in the DKC1 gene are responsible for causing DKC, as well as a more severe allelic variant of the disease, Hoyeraal-Hreidarsson syndrome (HHS). The protein dyskerin is a highly conserved nucleolar protein that functions in rRNA biogenesis and possibly also in the processing of the RNA component (hTR) of the telomerase complex. AIMS: To contribute towards unraveling the functions of dyskerin in conjunction with disease progression, we sought to determine the in situ tissue- and developmental-specific expression pattern of DKC1. METHODS: This was accomplished by performing RNA in situ hybridizations on 10.5-18.5 dpc mouse embryos and on adult mouse tissue sections. RESULTS: A ubiquitous expression of Dkc1 was detected at all stages of development with notably higher expression confined not only to epithelia, but also to specific quiescent neurons in the adult brain (Purkinje cells, mitral cells). CONCLUSIONS: These results indicate that some of the pertinent functions of dyskerin may be more tissue-specific than previously thought and are not limited to rapidly dividing cells. Although it has been proposed that DKC could be a telomere maintenance disorder, it remains a challenge to understand the disease mechanism with respect to the various mutations. We are therefore in the process of generating mouse models of the disease.

KEY WORDS: prognostics and diagnostics, pre-mature aging syndrome, stem cell defect, chromosomal instability, cell senescence, coiled bodies (extranucleolar structures).

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Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on genetic risk assessment.