Journal
NEUROBIOLOGY OF AGING
Volume 36, Issue 1, Pages -Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2014.08.021
Keywords
CADASIL; NOTCH3; Stroke; Dementia; Genetic
Categories
Funding
- Federico II University of Naples, Italy
- Niguarda Ca'Grande Hospital, Milan, Italy
- University of Verona, Italy
- University Parthenope, Naples, Italy
- Boehringer Ingelheim
- Novartis
- Schwarz Pharma/UCB
- Merck-Serono
- Solvay
- Lundbeck
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The cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is because of NOTCH3 mutations affecting the number of cysteine residues. In this view, the role of atypical NOTCH3 mutations is still debated. Therefore, we investigated a family carrying a NOTCH3 nonsense mutation, with dominantly inherited recurrent cerebrovascular disorders. Among 7 family members, 4 received a clinical diagnosis of CADASIL. A heterozygous truncating mutation in exon 3 (c.307C>T, p.Arg103X) was found in the 4 clinically affected subjects and in one 27-year old lady, only complaining of migraine with aura. Magnetic resonance imaging scans found typical signs of small-vessel disease in the 4 affected subjects, supporting the clinical diagnosis. Skin biopsies did not show the typical granular osmiophilic material, but only nonspecific signs of vascular damage, resembling those previously described in Notch3 knockout mice. Interestingly, messenger RNA (mRNA) analysis supports the hypothesis of an atypical NOTCH3 mutation, suggesting a nonsense-mediated mRNA decay. In conclusion, the present study broadens the spectrum of CADASIL mutations, and, therefore, opens new insights about Notch3 signaling. (C) 2015 Elsevier Inc. All rights reserved.
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