Gene Dosage Effect on γ-Secretase Component Aph-1b in a Rat Model for Neurodevelopmental Disorders

• DOI: 10.1016/j.neuron.2004.12.054
• Publication Date: 2005-02-18T07:50:59Z
• Authors: Marcel W. Coolen; Karen M.J. Van Loo; Nick N.H.M. Van B...; David J. Pulford; Lutgarde Serneels; Bart De Strooper; Bart A. Ellenbroek; Alexander R. Cools; Gerard J.M. Martens
• Keywords: Gene dosage

A combination of genetic factors and early life events is thought to determine the vulnerability of an individual to develop a complex neurodevelopmental disorder like schizophrenia. Pharmacogenetically selected, apomorphine-susceptible Wistar rats (APO-SUS) display a number of behavioral and pathophysiological features reminiscent of such disorders. Here, we report microarray analyses revealing in APO-SUS rats, relative to their counterpart APO-UNSUS rats, a reduced expression of Aph-1b, a component of the gamma-secretase enzyme complex that is involved in multiple (neuro)developmental signaling pathways. The reduced expression is due to a duplicon-based genomic rearrangement event resulting in an Aph-1b dosage imbalance. The expression levels of the other gamma-secretase components were not affected. However, gamma-secretase cleavage activity was significantly changed, and the APO-SUS/-UNSUS Aph-1b genotypes segregated with a number of behavioral phenotypes. Thus, a subtle imbalance in the expression of a single, developmentally important protein may be sufficient to cause a complex phenotype.