TY - JOUR
T1 - Homozygous NOTCH3 null mutation and impaired NOTCH3 signaling in recessive early-onset arteriopathy and cavitating leukoencephalopathy
AU - Pippucci, Tommaso
AU - Maresca, Alessandra
AU - Magini, Pamela
AU - Cenacchi, Giovanna
AU - Donadio, Vincenzo
AU - Palombo, Flavia
AU - Papa, Valentina
AU - Incensi, Alex
AU - Gasparre, Giuseppe
AU - Valentino, Maria Lucia
AU - Preziuso, Carmela
AU - Pisano, Annalinda
AU - Ragno, Michele
AU - Liguori, Rocco
AU - Giordano, Carla
AU - Tonon, Caterina
AU - Lodi, Raffaele
AU - Parmeggiani, Antonia
AU - Carelli, Valerio
AU - Seri, Marco
PY - 2015/6/1
Y1 - 2015/6/1
N2 - 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.
AB - 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.
KW - CADASIL
KW - Cerebral arteriopathy
KW - Exome
KW - Leukoencephalopathy
KW - NOTCH3
UR - http://www.scopus.com/inward/record.url?scp=84930180640&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84930180640&partnerID=8YFLogxK
U2 - 10.15252/emmm.201404399
DO - 10.15252/emmm.201404399
M3 - Article
AN - SCOPUS:84930180640
VL - 7
SP - 848
EP - 858
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
SN - 1757-4676
IS - 6
ER -