Areas of research

Hereditary diseases of the small cerebral arteries of unknown cause

Hereditary diseases of the small cerebral arteries of unknown cause. Identification of the relevant genes based on a "candidate-gene" approach focusing on the Notch3 signaling path and on a "reverse genetics" approach.

PHRC 2006
Starting date: Mid 2007
Completion date: End of 2010

Principal Investigator: Professor Elizabeth Tournier-Lasserve, Histo-Embryo-Cytogenetics and Molecular Genetics Laboratory, Lariboisière Hospital, Paris.

Rationale: Several rare hereditary forms of disease of the small cerebral arteries have been individually defined, based on their clinical, radiological and/or sometimes molecular characteristics. This sub-group includes:

  • autosomal dominant cerebral amyloid angiopathy usually responsible for strokes;
  • autosomal dominant cerebro-retinal angiopathy;
  • CARASIL, the only know recessive form, in which the neuro-vascular damage is associated with extra-neurological signs;
  • CADASIL caused by stereotyped mutations of the gene coding for the Notch3 receptor, which is the commonest of these hereditary diseases.

Samples from several hundred unrelated patients from all over France are sent to the Genetics Laboratory at Lariboisière every year for molecular diagnosis of small artery disease of unknown cause. A mutation is detected in 15-20% of these samples, almost always a mutation in the Notch3 gene (unpublished data). The information obtained from patients without any identified mutation strongly suggests that some of these patients are affected by other hereditary forms of disease of small cerebral arteries whose genetic origins are as yet unknown. Our team has recently identified two new autosomal dominant hereditary forms of disease of small cerebral arteries.

Objective: The aim of the research is to identify the genes involved in hereditary diseases of the small arteries for which other possible diagnoses have been dismissed.

Selection of patients and families: Using families who have already been identified, clinical data and MRIs of patients and their relatives will specify the mode of transmission of the disease.

Strategy: The approach used to identify the mutated genes in these families will be twofold and based on:

  • The screening of candidate genes, in particular the genes involved in the Notch3 signalling pathway. The identification of these genes is the subject of a major research programme led by Dr A. Joutel within the framework of this project.
  • A "reverse genetics" approach to locate the mutated gene and identify it without any prior presumptions as to its function.