title: Hypomorphic NOTCH3 mutation in an Italian family with CADASIL features.
abstract: 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.
authors.affiliation: Department of Neuroscience, Reproductive Science and Odontostomatology, Federico II University, Naples, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Moccia
authors.affiliation: Medical Genetics Unit, Department of Laboratory Medicine, Niguarda Ca'Granda Hospital, Milan, Italy.
authors.forename: Lorena
authors.initials: L
authors.lastname: Mosca
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, UK.
authors.forename: Roberto
authors.initials: R
authors.lastname: Erro
authors.affiliation: Department of Advanced Biomedical Sciences, Anatomopathology Unit, Federico II University, Naples, Italy.
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: Cervasio
authors.affiliation: Department of Neuroscience, Reproductive Science and Odontostomatology, Federico II University, Naples, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Allocca
authors.affiliation: Department of Motor Sciences, University of Naples "Parthenope," Naples, Italy; Istituto di Diagnosi e Cura (IDC) Hermitage-Capodimonte, Naples, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Vitale
authors.affiliation: Department of Molecular and Biotechnological Medicine, Federico II University, Naples, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Leonardi
authors.affiliation: Department of Advanced Biomedical Sciences, Neuroradiology Unit, Federico II University, Naples, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Caranci
authors.affiliation: Department of Advanced Biomedical Sciences, Anatomopathology Unit, Federico II University, Naples, Italy.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Del Basso-De Caro
authors.affiliation: Center for Neurodegenerative Diseases (CEMAND), Neuroscience Section, Department of Medicine, University of Salerno, Salerno, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Barone
authors.affiliation: Medical Genetics Unit, Department of Laboratory Medicine, Niguarda Ca'Granda Hospital, Milan, Italy. Electronic address: silvana.penco@ospedaleniguarda.it.
authors.forename: Silvana
authors.initials: S
authors.lastname: Penco
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D046589:CADASIL / Q000235:genetics*; D018389:Codon, Nonsense; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D007558:Italy; D008297:Male; D051379:Mice; D008875:Middle Aged; D012333:RNA, Messenger; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D055815:Young Adult
chemical_list: D018389:Codon, Nonsense; C499374:NOTCH3 protein, human; D012333:RNA, Messenger; D000071656:Receptor, Notch3; D051880:Receptors, Notch
keywords: CADASIL; Dementia; Genetic; NOTCH3; Stroke