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

EMBO Molecular Medicine

Tommaso Pippucci³  Alessandra Maresca⁶  Pamela Magini⁵  Giovanna Cenacchi¹  Vincenzo Donadio⁶  Flavia Palombo⁵  Valentina Papa¹  Alex Incensi⁶  Giuseppe Gasparre⁵  Maria Lucia Valentino⁶  Carmela Preziuso⁴  Annalinda Pisano⁴  Michele Ragno²  Rocco Liguori⁶  Carla Giordano⁴  Caterina Tonon¹  Raffaele Lodi¹  Antonia Parmeggiani⁵  Valerio Carelli⁶ 

[1] Unita' di Neurologia, Dipartimento di Scienze Biomediche e Neuromotorie (DIBINEM), University of Bologna, Bologna, Italy;Divisione di Neurologia, Ospedale Mazzoni, Azienda Sanitaria Unica Regionale, Ascoli Piceno, Italy;U.O. Genetica Medica, Policlinico Sant'Orsola-Malpighi, Bologna, Italy;Dipartimento di Scienze Radiologiche, Oncologiche ed Anatomopatologiche, Sapienza, University of Rome, Rome, Italy;Dipartimento di Scienze Mediche Chirurgiche (DIMEC), University of Bologna, Bologna, Italy;IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy

关键词: CADASIL;    cerebral arteriopathy;    exome;    leukoencephalopathy;    NOTCH3;   

DOI  :  10.15252/emmm.201404399

来源: Wiley

【 摘 要 】

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.

Synopsis

A recessive homozygous protein-truncating NOTCH3 mutation is found in a patient with devastating childhood-onset, vascular leukoencephalopathy, suggesting that this could be the underlying mechanism in other patients with similar severe pathology.

• For the first time, a recessive homozygous protein-truncating mutation in NOTCH3 has been found in a patient with a devastating childhood-onset, vascular leukoencephalopathy.
• This mutation is shown to abolish NOTCH3 expression and signaling, with downregulation of NOTCH3 target genes.
• In the patient, vessels were characterized by SMC degeneration, similar to that observed in CADASIL. However, GOM deposits, the CADASIL hallmark, were absent, mirroring the Notch3^−/− mouse model.
• Both the heterozygous consanguineous parents displayed similar but less dramatic trends in NOTCH3 signaling impairment and vascular damage.

【 授权许可】

CC BY   
© 2015 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.