0-TESTO COMPLETO.pdf - Fondazione Santa Lucia

RF07.66 – The italian ALS genetic collaborative project: follow-up genetic association study…
– Schymick JC et al. (2007) Lancet Neurol 6:322-328.
– Gwinn K et al. (2007) PLoS ONE. 2:e1254.
– Dunckley T et al. (2007) N Engl J Med 357:775-788.
What the project adds to the information already available
This study will identify genes that underlie this commoner sporadic form
of ALS. Such information will be highly relevant to the ALS research community
as it will identify novel metabolic pathways involved in neurodegeneration.
Ultimately, this will identify an array of novel drugable targets and facilitate
the development of new therapeutic agents effective in slowing disease
progression.
The information provided by this study will also be useful in clinical practice,
and, in particular, will allow more rapid diagnosis of ALS patients in the
early stages of their disease and will provide useful data for genetic counseling
of relatives of ALS patients concerned about their risk of developing disease.
Based on the concept that interactive network of modified gene products may
be responsible for the dysfunctional state of motor neurons, we will verify in
the cell and animal models of the motor neuron degeneration whether and
how the susceptible genes may interact with mutant SOD1.
OBJECTIVE(S)
1. To determine which of the 7,600 most significant SNPs identified in
the whole-genome association studies of American and Italian sporadic ALS
patients are truly associated with an increased risk of sporadic ALS by genotyping
these SNPs in a large new cohort of 2,304 American and European
sporadic ALS cases and 2,304 controls using the customizable Illumina iSelect
SNP genotyping chip.
2. To perform the sequencing of the genes identified in the first WGA
study (the 4 most significant genes in the American and Italian ALS populations)
and in the iSelect study (all the genes which will result truly associated
with ALS).
3. To assess in the whole population of Italian ALS patients included in
the iSelect study whether the genes are related to relevant clinical factors (age
at onset, site of onset, rate of progression of ALS, survival, other phenotypic
characteristics).
4. To verify in the cell and animal models of the motor neuron degeneration
whether and how the susceptibility genes may interact with mutant
SOD1 (phenotypic characteristics as onset, progression, death, as well as morphological
characteristics).
GENERAL TRANSFERIBILITY AND POTENTIAL IMPACT OF RESULTS
The current project represents a continuation of the significant work that
has already completed by genotyping a large cohort of American and Italians
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