NOTCH3 – CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic small-vessel disease characterized by recurrent stroke episodes, migraine, and progressive dementia. The disorder follows an autosomal dominant inheritance pattern and is caused by pathogenic variants in the NOTCH3 gene, encoding a transmembrane receptor with 34 EGF-like repeats essential for vascular smooth muscle cell integrity.

Extensive genetic studies have identified over 100 unique cysteine-altering missense variants in NOTCH3 across diverse populations, leading to a loss or gain of a cysteine residue within EGF repeats and resulting in misfolding and accumulation of the NOTCH3 extracellular domain (ECD) in vessel walls. In a cohort of 50 unrelated CADASIL patients, 90% carried stereotyped cysteine-altering variants clustered in exons encoding the first five EGF repeats (PMID:9388399). Founder effects have been documented, such as the R133C variant in Finnish families (PMID:15378071) and the R90C variant in a four-generation Turkish kindred with 12 affected individuals (PMID:11784372).

Segregation analyses in multiple pedigrees demonstrate clear cosegregation of NOTCH3 variants with disease. For example, the R90C mutation tracked through 12 affected relatives in four generations, supporting autosomal dominant transmission and high penetrance in mid-adult life (PMID:11784372). De novo occurrences (e.g., Arg182Cys) further underscore the variant-centric etiology and caution against excluding CADASIL in sporadic cases (PMID:10716263).

Functional studies reveal that cysteine-altering mutations impair NOTCH3 trafficking and maturation, promote detergent-insoluble ECD aggregation, and alter ligand binding without uniformly abolishing canonical signaling. The R141C mutation exhibits impaired intracellular trafficking and reduced cell-surface expression (PMID:12482954), while mutant ECD recruits extracellular matrix proteins such as TIMP3 and vitronectin into vessel wall aggregates, contributing to vascular pathology (PMID:23649698).

Animal models expressing the archetypal R90C mutant demonstrate that the variant retains signaling function in vivo, indicating a gain-of-toxic-function mechanism rather than simple loss of receptor activity (PMID:17331978). Hypomorphic alleles (e.g., C455R and R1031C) in transgenic mice link reduced NOTCH3 activity to age-dependent ischemic small-vessel disease and granular osmiophilic material pathology, mirroring human CADASIL (PMID:21555590).

Although most reported mutations alter cysteine residues, cysteine-sparing variants have been observed in atypical presentations and remain of uncertain significance, highlighting the need for functional validation and careful clinical correlation (PMID:23597439).

Integration of genetic and experimental data establishes a definitive gene–disease relationship between NOTCH3 and CADASIL. The high frequency of recurrent, pathogenic cysteine-altering variants, clear familial segregation, and concordant mechanistic studies support robust diagnostic and prognostic use of NOTCH3 testing in clinical practice. Key Take-home: CADASIL should be suspected in adults with subcortical infarcts, migraine, leukoencephalopathy, or early dementia—genetic testing for cysteine-altering NOTCH3 variants provides a reliable diagnostic tool and guides family counseling.

References

• Lancet • 1997 • Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients PMID:9388399
• European journal of neurology • 2002 • CADASIL syndrome in a large Turkish kindred caused by the R90C mutation in the Notch3 receptor PMID:11784372
• Proc Natl Acad Sci U S A • 2002 • A CADASIL-mutated Notch 3 receptor exhibits impaired intracellular trafficking and maturation but normal ligand-induced signaling PMID:12482954
• Brain • 2013 • Abnormal recruitment of extracellular matrix proteins by excess Notch3 ECD: a new pathomechanism in CADASIL PMID:23649698
• Proc Natl Acad Sci U S A • 2007 • The archetypal R90C CADASIL-NOTCH3 mutation retains NOTCH3 function in vivo PMID:17331978
• Proc Natl Acad Sci U S A • 2011 • Hypomorphic Notch 3 alleles link Notch signaling to ischemic cerebral small-vessel disease PMID:21555590

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