title: Homozygous NOTCH3 null mutation and impaired NOTCH3 signaling in recessive early-onset arteriopathy and cavitating leukoencephalopathy.
abstract: Notch signaling is essential for vascular physiology. Neomorphic heterozygous mutations in NOTCH3, one of the four human NOTCH receptors, cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Hypomorphic heterozygous alleles have been occasionally described in association with a spectrum of cerebrovascular phenotypes overlapping CADASIL, but their pathogenic potential is unclear. We describe a patient with childhood-onset arteriopathy, cavitating leukoencephalopathy with cerebral white matter abnormalities presented as diffuse cavitations, multiple lacunar infarctions and disseminated microbleeds. We identified a novel homozygous c.C2898A (p.C966*) null mutation in NOTCH3 abolishing NOTCH3 expression and causing NOTCH3 signaling impairment. NOTCH3 targets acting in the regulation of arterial tone (KCNA5) or expressed in the vasculature (CDH6) were downregulated. Patient's vessels were characterized by smooth muscle degeneration as in CADASIL, but without deposition of granular osmiophilic material (GOM), the CADASIL hallmark. The heterozygous parents displayed similar but less dramatic trends in decrease in the expression of NOTCH3 and its targets, as well as in vessel degeneration. This study suggests a functional link between NOTCH3 deficiency and pathogenesis of vascular leukoencephalopathies.
authors: U.O. Genetica Medica, Policlinico Sant'Orsola-Malpighi, Bologna, Italy Dipartimento di Scienze Mediche Chirurgiche (DIMEC), University of Bologna, Bologna, Italy.
authors: Tommaso
authors: T
authors: Pippucci
authors: IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy Unita' di Neurologia, Dipartimento di Scienze Biomediche e Neuromotorie (DIBINEM), University of Bologna, Bologna, Italy.
authors: Alessandra
authors: A
authors: Maresca
authors: Dipartimento di Scienze Mediche Chirurgiche (DIMEC), University of Bologna, Bologna, Italy.
authors: Pamela
authors: P
authors: Magini
authors: Unita' di Neurologia, Dipartimento di Scienze Biomediche e Neuromotorie (DIBINEM), University of Bologna, Bologna, Italy.
authors: Giovanna
authors: G
authors: Cenacchi
authors: IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
authors: Vincenzo
authors: V
authors: Donadio
authors: Dipartimento di Scienze Mediche Chirurgiche (DIMEC), University of Bologna, Bologna, Italy.
authors: Flavia
authors: F
authors: Palombo
authors: Unita' di Neurologia, Dipartimento di Scienze Biomediche e Neuromotorie (DIBINEM), University of Bologna, Bologna, Italy.
authors: Valentina
authors: V
authors: Papa
authors: IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
authors: Alex
authors: A
authors: Incensi
authors: Dipartimento di Scienze Mediche Chirurgiche (DIMEC), University of Bologna, Bologna, Italy.
authors: Giuseppe
authors: G
authors: Gasparre
authors: IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy Unita' di Neurologia, Dipartimento di Scienze Biomediche e Neuromotorie (DIBINEM), University of Bologna, Bologna, Italy.
authors: Maria Lucia
authors: ML
authors: Valentino
authors: Dipartimento di Scienze Radiologiche, Oncologiche ed Anatomopatologiche, Sapienza, University of Rome, Rome, Italy.
authors: Carmela
authors: C
authors: Preziuso
authors: Dipartimento di Scienze Radiologiche, Oncologiche ed Anatomopatologiche, Sapienza, University of Rome, Rome, Italy.
authors: Annalinda
authors: A
authors: Pisano
authors: Divisione di Neurologia, Ospedale Mazzoni, Azienda Sanitaria Unica Regionale, Ascoli Piceno, Italy.
authors: Michele
authors: M
authors: Ragno
authors: IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy Unita' di Neurologia, Dipartimento di Scienze Biomediche e Neuromotorie (DIBINEM), University of Bologna, Bologna, Italy.
authors: Rocco
authors: R
authors: Liguori
authors: Dipartimento di Scienze Radiologiche, Oncologiche ed Anatomopatologiche, Sapienza, University of Rome, Rome, Italy.
authors: Carla
authors: C
authors: Giordano
authors: Unita' di Neurologia, Dipartimento di Scienze Biomediche e Neuromotorie (DIBINEM), University of Bologna, Bologna, Italy Unità Risonanza Magnetica Funzionale, Policlinico S.Orsola-Malpighi, Bologna, Italy.
authors: Caterina
authors: C
authors: Tonon
authors: Unita' di Neurologia, Dipartimento di Scienze Biomediche e Neuromotorie (DIBINEM), University of Bologna, Bologna, Italy Unità Risonanza Magnetica Funzionale, Policlinico S.Orsola-Malpighi, Bologna, Italy.
authors: Raffaele
authors: R
authors: Lodi
authors: Dipartimento di Scienze Mediche Chirurgiche (DIMEC), University of Bologna, Bologna, Italy U.O. Neuropsichiatria Infantile, Policlinico S.Orsola-Malpighi, Bologna, Italy.
authors: Antonia
authors: A
authors: Parmeggiani
authors: IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy Unita' di Neurologia, Dipartimento di Scienze Biomediche e Neuromotorie (DIBINEM), University of Bologna, Bologna, Italy valerio.carelli@unibo.it marco.seri@unibo.it.
authors: Valerio
authors: V
authors: Carelli
authors: U.O. Genetica Medica, Policlinico Sant'Orsola-Malpighi, Bologna, Italy Dipartimento di Scienze Mediche Chirurgiche (DIMEC), University of Bologna, Bologna, Italy valerio.carelli@unibo.it marco.seri@unibo.it.
authors: Marco
authors: M
authors: Seri
mesh_terms: D000328:Adult; D000505:Alopecia / Q000235:genetics* / Q000473:pathology*; D015820:Cadherins / Q000032:analysis; D002544:Cerebral Infarction / Q000235:genetics* / Q000473:pathology*; D015536:Down-Regulation; D006579:Heterozygote; D006651:Histocytochemistry; D006801:Humans; D007150:Immunohistochemistry; D051666:Kv1.5 Potassium Channel / Q000032:analysis; D056784:Leukoencephalopathies / Q000235:genetics* / Q000473:pathology*; D046529:Microscopy, Electron, Transmission; D018482:Muscle, Skeletal / Q000473:pathology; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000172:deficiency*; D012867:Skin / Q000473:pathology; D013122:Spinal Diseases / Q000235:genetics* / Q000473:pathology*; D055815:Young Adult
chemical_list: D015820:Cadherins; C496981:KCNA5 protein, human; D051666:Kv1.5 Potassium Channel; C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch; C087310:K cadherin
keywords: CADASIL; NOTCH3; cerebral arteriopathy; exome; leukoencephalopathy