Considerations on a mutation in the NOTCH3 gene sparing a cysteine residue: a rare polymorphism rather than a CADASIL variant

Abstract

Some missense mutations and small deletions in the NOTCH3 gene, not involving cysteine residues, have been described in patients considered to be affected by paucisymptomatic CADASIL. However, the significance of such molecular variants is still unclear. We describe a 49-year-old woman with a CADASIL-like phenotype, carrying a novel cysteine-sparing mutation in exon 29 of the NOTCH3 gene, and discuss the possible pathogenetic role of this molecular variant. Even though atypical clinical and MRI findings make a diagnosis of CADASIL unlikely in this patient, our report nevertheless underlines the intriguing genotype-phenotype relationship in NOTCH3 mutations and the importance of functional investigation to ascertain the role of new NOTCH3 mutations in CADASIL pathogenesis.

Figure 1

Patient’s brain MRI DP and T2-weighted MRI showing diffuse hyperintensities in the pons (black arrows) and the deep and periventricular white matter (white arrows). Note the absence of involvement of the anterior temporal pole and of the external capsule.

Figure 2

Family pedigree The pedigree of the family analyzed is shown in the upper left part of the figure. Asterisks indicate the subjects from whom DNA was obtained. The arrow indicates the proband. Rhombic symbols are used for privacy reasons. Electropherograms of the sequence encompassing the nucleotide change in the patient (PT) with respect to the control (CTRL) are shown on the right. At the bottom the alignment of the Nothc3 homologs from different species is shown: NP_000426 H. sapiens; XP_853041 C. lupus familiaris; NP_032742 M. musculus; NP_064472 R. norvegicus; NP_571624 D. rerio.