Human Molecular Genetics Advance Access originally published online on May 5, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 13 1321-1331
DOI: 10.1093/hmg/ddh151
Human Molecular Genetics, Vol. 13, No. 13 © Oxford University Press 2004; all rights reserved
Partial loss of presenilins causes seborrheic keratosis and autoimmune disease in mice
1Neuronal Cell Biology Laboratory, Center for Human Genetics CB 4, 2Department of Laboratory Medicine, University Hospital and 3Department of Dermatology, Catholic University of Leuven, Herestraat 49, B-3000 Leuven, Belgium, 4Flanders Institute for Biotechnology VIB IV, Herestraat 49, B-3000 Leuven, Belgium and 5Department of Biochemistry, CAU Kiel, Olshausenstrasse 40, D-24118 Kiel, Germany
Received February 12, 2004; Revised April 1, 2004; Accepted April 26, 2004
Presenilin (PS1) and (PS2) are the centers of 
-secretase that release Aß from APP in Alzheimer's disease (AD). They cleave signaling proteins like Notch and downregulate ß-catenin to modulate Wnt signaling. Inactivation of PS1 or PS1 and PS2 causes a prenatally lethal ‘Notch phenotype,’ which has hampered investigation of PS function in adulthood seriously. We have thus turned towards PS1+/–PS2–/– mice which carry the most severe reduction of PS alleles compatible with survival, to analyze the consequences of impaired PS function especially in adulthood. In these ‘partial deficient’ mice, PS1 protein concentration is considerably lowered, functionally reflected by reduced -secretase activity and impaired ß-catenin downregulation. Their phenotype is normal up to 
6 months, when the majority of the mice develop an autoimmune disease characterized by dermatitis, glomerulonephritis, keratitis and vasculitis, as seen in human systemic lupus erythematosus. Besides B-cell dominated infiltrates, we observe a hypergammaglobulinemia with immune complex deposits in several tissues, high-titer nuclear autoantibodies and an increased CD4+/CD8+ ratio. The mice further develop a benign skin hyperplasia similar to human seborrheic keratosis as opposed to malignant keratocarcinomata observed in skin-specific PS1 ‘full’ knockouts. A partial reduction of PS function in PS1+/–PS2–/– mice causes a novel phenotype in adulthood unrelated to the developmental defects of full knockouts. As PS1+/–PS2+/– mice remain healthy, this points towards a sharply defined minimum of PS function. Skin and immune system appear to be especially sensitive targets of impaired PS function and may need careful monitoring if -secretase inhibitors are envisaged for treating AD.
* To whom correspondence should be addressed at: Neuronal Cell Biology Laboratory, Center for Human Genetics CB 4, Catholic University of Leuven, Herestraat 49, B-3000 Leuven, Belgium. Tel: +32 16345994; Fax: +32 16347181; Email: dieter.hartmann{at}med.kuleuven.ac.be
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