Objective
- Development of a novel cloning strategy for CAG repeat expansions.
- Identification of CAG repeat expansion in neuropsychiatric disorders and bipolar affective disorder (BPAD).
- Isolation of the gene(s) containing these expanded repeats.
- Characterization of the structure and function of the identified gene(s).
- Modelling of interactions with other genes or factors of importance to the disease.
Several groups have demonstrated genetic anticipation (a marked decrease in age at onset or an increased disease severity observed when comparing subsequent generations of affected individuals in a family) in neuropsychiatric disorders. This is particularly striking in families segregating bipolar affective disorder (BPAD). Anticipation is also present in a number of brain disorders caused by expanding trinucleotide DNA sequences. We suggest that such sequences may be pathologically expanded in BPAD. We will screen for, clone and characterise genes containing DNA repeat expansions in neuropsychiatric disorders in BPAD.
We will use clinically well-characterised patient material to identify genes containing expanded trinucelotide repeat sequences in BPAD and neuropsychiatric disorders. Initially, we will screen for the occurrence of expanded CAG repeat sequences segregating with BPAD and major affective disorders using the repeat expansion detection (RED) method. The RED method is an amplification method to detect repeat sequences >/= 120 base pairs in genomic DNA. Cell lines will be established from multiple members of families suitable for subsequent study. Genomic DNA from these cell lines will then be used to obtain a single copy DNA sequence flanking the expanded repeat sequence. This will be accomplished by sucrose gradient centrifugation and analysis with the RED method to isolate fractions containing the expanded repeat sequence, thereby reducing the complexity of the genome. Positive fractions will be analysed using gel electrophoresis to physically separate all remaining CAG sequences. The expanded repeat sequence will be apparent in a 2-D gel system by its relatively higher intensity signal following stringent hybridization with a repeat oligonucleotide. Single copy flanking DNA sequence will subsequently be obtained from candidate spots. Following sequencing of DNA flanking the repeat, families will be tested for expansion at the isolated locus and radiation hybrid mapping will be used to identify the chromosomal locus. Brain cDNA isolation will follow, leading to gene identification, characterisation by sequence and expression pattern as well as functional analysis. Mutual gene interactions may be studied in families previously linked to a chromosomal locus.
The aim of this study is to provide improved understanding of biological factors involved in BPAD and to develop diagnostic tools for assessing vulnerability to neuropsychiatric disorders. Identification of target molecules involved in the pathogenesis of BPAD will open up new pharmaceutical strategies and improve health in the community. Furthermore, once established the technologies proposed here can be applied to any disease caused by a dynamic mutation.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences genetics DNA
- natural sciences biological sciences genetics mutation
- natural sciences mathematics pure mathematics mathematical analysis functional analysis
- natural sciences chemical sciences electrochemistry electrophoresis
- natural sciences biological sciences genetics genomes
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Coordinator
171 76 Stockholm
Sweden
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