Mutations described here cause an odd number of cysteines in the N-terminal of the EGF domain of Notch3 protein, which seems to have an important functional effect in the pathophysiology of CADASIL.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is caused by mutations in the <i>NOTCH3</i> gene which maps to the short arm of chromosome 19 and encodes the NOTCH3 receptor protein, predominantly expressed in adults by vascular smooth muscle cells and pericytes.
Given the dominant, highly penetrant and potentially serious effects of Notch3 mutations, PGD for CADASIL may be considered and implemented as a reproductive option, following proper genetic counseling.
Evaluation revealed white matter changes consistent with CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), and genetic testing showed a Notch3 gene mutation consistent with CADASIL.
Notably, 2 SVCI patients with NOTCH3 mutations showed significant amyloid burden, which challenges the prevailing concept that CADASIL represents the genetic model of pure small vessel disease.
Except for isolated cases of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy or CADASIL, hereditary arteriopathies have so far not been reported in Africa.
We generated transgenic mice in which the SM22alpha promoter drove, in VSMCs, the expression of a full-length human Notch3 carrying the Arg90Cys mutation, a CADASIL archetypal mutation.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is an inherited cerebrovascular disease due to mutations of the Notch3 gene at the chromosome locus 19p13.
No association between multiple sclerosis and the Notch3 gene responsible for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).
These data indicate that the CADASILNotch3 mutations were found in approximately 35% of familial cases with leukoencephalopathy, suggesting genetic heterogeneity of the disease.
Recent studies indicate that Notch3 gene mutations not only manifest as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) but also in the peripheral nerves and skeletal muscles.
Three human disorders including a neoplasia (a T-cell acute lymphoblastic leukemia/lymphoma), a late onset neurological disease (CADASIL) and a developmental disorder (the Alagille syndrome) are associated with mutations in, respectively, the Notch1, Notch3 and Jagged1 genes, pointing out the broad spectrum of Notch activity in humans.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary vascular small-vessel disease caused by Notch3 mutations and represents the most common form of hereditary stroke disorder.
The Notch3(Arg170Cys) mice displayed late-onset, dominant CADASIL arteriopathy with typical granular osmiophilic material deposition and developed brain histopathology including thrombosis, microbleeds, gliosis, and microinfarction.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an adult onset cerebral small vessel disorder caused by the mutations of the neurogenic locus notch homolog protein 3 (NOTCH3) gene.
To analyze the NOTCH3 gene mutations in patients from mainland China clinically suspected to have cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and evaluate large intracranial arteries in CADASIL patients.
Significantly more CADASIL patients with the NOTCH3Arg133Cys mutation had hyperintensity in the external capsule compared with CADASIL patients with the other mutations not including the NOTCH3 Arg75Pro mutation.