A novel Notch3 gene mutation not involving a cysteine residue in an Italian family with CADASIL

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebrovascular disease leading to accumulating neurologic deficits and dementia. CADASIL has been linked to nucleotide substitutions and deletions in the Notch3 gene. All the mutations described until now lead to unpaired cysteine residue in the epidermal growth factor-like repeats. The authors report a family with CADASIL carrying a deletion in the Notch3 gene that did not involve a cysteine residue.

The spectrum of Notch3 mutations in 28 Italian CADASIL families

“…Eighteen different mutation sites were detected in the 28 index cases, and seven novel mutations were identified: one deletion in each of exons 3 8 …”

“…5 The deletion on exon 3 did not involve a cysteine residue. 8 CADASIL is an increasingly recognised hereditary cerebrovascular pathology leading to progressive neurological handicap. The wide variability in clinical presentation and evolution, the apparent absence of inheritance in many cases, and the substantially non-specific pattern of MRI lesions, at least in the early stages, make clinical diagnosis difficult.…”

Cysteine-Sparing CADASIL Mutations in NOTCH3 Show Proaggregatory Properties In Vitro

“…∆88-91, although identified so far only in a single Italian family, can be considered as sufficiently documented based on the available genetic, clinical, and histological data. 18 On the other hand, multimerization was absent for R61W and R213K. Intriguingly, the clinical significance of these mutations can be questioned.…”

Two Japanese CADASIL Families Exhibiting Notch3 Mutation R75P Not Involving Cysteine Residue

“…CADASIL is caused by single missense mutations (2)(3)(4)(5), small in-frame deletions (6,7), or splice site mutations (8) in the Notch3 gene. Most previously reported mutations have resulted in an odd number of cysteine residues within the first five EGF-like repeats (4,9).…”