NOTCH3 variant position is associated with NOTCH3 aggregation load in CADASIL vasculature

Area of Science:

• Neurology
• Genetics
• Vascular Biology

Background:

• Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary cerebral small vessel disease.
• It results from cysteine-altering NOTCH3 variants (NOTCH3^cys) causing vascular NOTCH3 protein aggregation.
• Variants in NOTCH3 epidermal growth-factor like repeat (EGFr) domains 1-6 are linked to more severe CADASIL phenotypes than those in EGFr domains 7-34.

Purpose of the Study:

• To investigate if the position of NOTCH3^cys variants correlates with the degree of NOTCH3 protein aggregation in CADASIL patients.
• To explore the underlying mechanisms of genotype-phenotype correlations in CADASIL.

Main Methods:

• Quantified vascular NOTCH3 aggregation in skin biopsies (n=25) and brain tissue (n=7) from CADASIL patients.
• Utilized NOTCH3 immunohistochemistry (NOTCH3 score) and ultrastructural analysis of granular osmiophilic material (GOM count).
• Assessed disease severity using neuroimaging (lacune count, white matter hyperintensity volume) and the modified Rankin scale.

Main Results:

• Patients with NOTCH3^cys EGFr 7-34 variants exhibited significantly lower NOTCH3 scores and GOM counts in skin vasculature compared to those with EGFr 1-6 variants (P < 1.3·10^-5).
• A similar trend in reduced NOTCH3 aggregation was observed in brain vasculature.
• In the EGFr 7-34 group, aggregation levels correlated with lacune count (P=0.03) and white matter hyperintensity volume (P=0.02), but not disability.

Conclusions:

• CADASIL patients with EGFr 7-34 variants demonstrate substantially less vascular NOTCH3 aggregation compared to those with EGFr 1-6 variants.
• This difference in protein aggregation may contribute to the observed variations in disease severity between these genetic groups.