Homozygous NOTCH3 null mutation and impaired NOTCH3 signaling in recessive early-onset arteriopathy and cavitating leukoencephalopathy

Tommaso Pippucci, Alessandra Maresca, Pamela Magini, Giovanna Cenacchi, Vincenzo Donadio, Flavia Palombo, Valentina Papa, Alex Incensi, Giuseppe Gasparre, Maria Lucia Valentino, Carmela Preziuso, Annalinda Pisano, Michele Ragno, Rocco Liguori, Carla Giordano, Caterina Tonon, Raffaele Lodi, Antonia Parmeggiani, Valerio Carelli, Marco Seri

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)848-858
Number of pages11
JournalEMBO Molecular Medicine
Issue number6
Publication statusPublished - Jun 1 2015


  • Cerebral arteriopathy
  • Exome
  • Leukoencephalopathy
  • NOTCH3

ASJC Scopus subject areas

  • Molecular Medicine


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