Loss-of-function Mutation in the NOTCH3 Gene: Simply a Polymorphism?


CADASIL, the most common heritable small vessel disease (SVD) of the brain, is caused by dominant mutations in the NOTCH3 receptor. Mutations can be unambiguously classified as pathogenic when they lead to an uneven number of cysteine residues in one of the 34 EGFR domains constituting the extracellular domain of the receptor. Yet, all others should be called unclassified variants at first observation.

In this issue, Rutten et al. (Hum Mutat 34:1486–1489) report two novel variants with predicted loss of NOTCH3 function. A nonsense mutation in exon 3 was identified in a 55-year-old patient with a history of ischemic strokes. However, the pattern of MRI lesions speaks against a SVD, and both immunohistochemical analysis and ultrastructural examination of skin vessels were negative for Notch3ECD and GOM deposits, the two hallmark pathologies of CADASIL. Moreover, the authors detected this nonsense mutation in the patient's 50-year-old brother, who has normal clinical and neuroradiological evaluation, while white-matter lesions on MRI are part of the core features of CADASIL and are always present in mutation carriers beyond 35 years of age. The second mutation, an intragenic heterozygous frameshit deletion of exons 3–16, was detected in a patient who harbors a typical pathogenic NOTCH3 mutation on the other allele. The phenotype of this latter patient was reported to be within the normal CADASIL spectrum, although this conclusion should be tempered by the large variability in the natural history of CADASIL.

Ruther et al. have shown for the first time that a mutation with predicted loss of NOTCH3 function is not causative for CADASIL. Large consecutive series with fully annotated clinical and MRI findings are required to clarify whether such mutations are actually neutral polymorphisms, or, causative for a distinct cerebrovascular entity, which may have an incomplete penetrance. Notwithstanding the toxic gain of function properties of mutant NOTCH3 in CADASIL, whether the loss of essential NOTCH3 function contributes to the phenotypic manifestations remains a controversial issue. Taken together, this work makes up one additional piece of evidence against the hypothesis that NOTCH3 haploinsufficiency is the driving force in CADASIL. However, further experimental studies are definitely needed to address this fundamental question.