NOTCH3 gene mutations in subjects clinically suspected of CADASIL

J Neurol Sci. 2011 Aug 15;307(1-2):144-8. doi: 10.1016/j.jns.2011.04.019. Epub 2011 May 26.

Abstract

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease due to mutations involving loss or gain of a cysteine residue in the NOTCH3 gene. A cluster of mutations around exons 3 and 4 was originally reported. Identification of pathogenic mutation is important for diagnostic confirmation of the disease, however genetic counselling and testing of relatives at risk is critical in mutation carriers.

Methods: Mutation analysis of the NOTCH3 gene was performed through direct sequencing in 140 patients with clinical suspicion of CADASIL. Patients underwent genetic counselling pre and post testing. The 2-23 exons containing all EGF-like domains were screened.

Results: 14 familial forms of the disease have been identified with 14 different causative mutations in exons 2, 3, 4, 5, 7, 10, 14, 19, 20 and 22 of the NOTCH3 gene; no pathogenetic mutations have been identified in exons 6 and 8; several genetic variations both in coding as well as in intronic regions were identified too.

Conclusions: Our data confirm the importance of screening the whole EGF-like domains region of NOTCH3 gene for the molecular diagnosis of CADASIL among the Italian population too. Moreover genetic variants different from loss or gain of a cysteine residue are identified and presented.

MeSH terms

  • Adult
  • Aged
  • Amino Acid Substitution / genetics
  • CADASIL / diagnosis*
  • CADASIL / genetics*
  • CADASIL / metabolism
  • Female
  • Genetic Predisposition to Disease / epidemiology
  • Genetic Predisposition to Disease / genetics*
  • Genetic Variation / genetics
  • Humans
  • Italy / epidemiology
  • Male
  • Middle Aged
  • Point Mutation / genetics*
  • Protein Structure, Tertiary / genetics
  • Receptor, Notch3
  • Receptors, Notch / deficiency
  • Receptors, Notch / genetics*
  • Young Adult

Substances

  • NOTCH3 protein, human
  • Receptor, Notch3
  • Receptors, Notch