![]() This finding was the basis for developing the 'NOTCH3 score', a quantitative measure for the NOTCH3 accumulation load. Immunohistochemistry on brain sections shows characteristic vascular human NOTCH3 accumulation in all four mutant strains, with human NOTCH3 RNA expression levels correlating with age at onset and progression of NOTCH3 accumulation. The four mutant strains we generated have respective human NOTCH3 RNA expression levels of 100, 150, 200 and 350 % relative to endogenous mouse Notch3 RNA expression. We generated transgenic mice in which we overexpressed the full length human NOTCH3 gene from a genomic construct with the archetypal c.544C > T, p.Arg182Cys mutation. To facilitate pre-clinical therapeutic interventions for CADASIL, we aimed to develop a novel, translational CADASIL mouse model. There is no therapy for CADASIL, and therapeutic development is hampered by a lack of feasible clinical outcome measures and biomarkers, both in mouse models and in CADASIL patients. ![]() The accumulation is systemic but most pronounced in the brain vasculature where it leads to clinical symptoms of recurrent stroke and dementia. (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a hereditary small vessel disease caused by mutations in the NOTCH3 gene, leading to toxic NOTCH3 protein accumulation in the small- to medium sized arterioles. 16 Department of Clinical Genetics, K5-R, Leiden University Medical Center, PO Box 9600, 2300, RC, Leiden, The Netherlands. 15 Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands. 14 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. 13 Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. 12 Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands. 11 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. 10 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. 9 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. 8 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. 7 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. 6 Department of Clinical Genetics, K5-R, Leiden University Medical Center, PO Box 9600, 2300, RC, Leiden, The Netherlands. 5 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. 4 Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands. 3 Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. 2 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. 1 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
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