Archetypal Arg169Cys Mutation in NOTCH3 Does Not Drive the Pathogenesis in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leucoencephalopathy via a Loss-of-Function Mechanism

Background and Purpose—Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy, the most common heritable small vessel disease of the brain, is caused by dominant mutations in the NOTCH3 receptor that stereotypically lead to age-dependent Notch3ECD deposition in the vessels. NOTCH3 loss of function has been demonstrated for few mutations. However, whether this finding applies to all mutations and whether a loss-of-function mechanism drives the manifestations of the disease remain yet unknown. This study investigated the in vivo functionality of the Arg169Cys archetypal mutation. Methods—We used mice with constitutive or conditional reduction of NOTCH3 activity, mice harboring the Arg169Cys mutation at the endogenous Notch3 locus (Notch3Arg170Cys), and mice overexpressing the Arg169Cys NOTCH3 mutant (TgPAC-Notch3R169C) on either a Notch3 wild-type or a null background. NOTCH3 activity was monitored in the brain arteries by measuring the expression of NOTCH3 target genes u...