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- W2014034634 abstract "Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are two extremes of the same disease spectrum. Most notable genetic evidence for this link came from the recent identification of G 4 C 2 repeat expansions in the promoter of C9orf72 as the most common cause of ALS and together with GRN and MAPT the third major gene for FTLD. Moreover, in FTLD-ALS C9orf72 is the first causal gene explaining the major part of familial FTLD-ALS. In brain, C9orf72 expression was significantly reduced by 50%. Different possible disease mechanisms were proposed including haploinsufficiency and RNA toxicity, and genotype-phenotype correlation studies are initiated. However, very little is known about the mutation spectrum, the genomic mechanism by which the C9orf72 G 4 C 2 repeat is expanding and the impact of repeat length on disease severity and susceptibility. We had independently identified the C9orf72 G 4 C 2 repeat expansion in a Flanders-Belgian cohort of 337 FTLD, 23 FTLD-ALS and 141 ALS patients. We calculated association between normal repeat length and disease and studied the correlation with the associated risk haplotype defined by SNP rs2814707. Further, we investigated whether a specific genomic background renders the repeat unstable and prone to expansion. In addition, we examined the presence of other loss-of-function mutations by exon-based sequencing and dosage analysis of C9orf72. We developed a novel STR genotyping assay and repeat-primed PCR assay to accurately size normal C9orf72 repeat alleles. We are assessing the effect of repeat length as a risk factor for FTLD-ALS spectrum diseases and evaluating potential molecular triggers for repeat instability and expansions. In addition, we are examining the loss-of-function hypothesis. To date, the mutation spectrum could not be extended to other types of loss-of-function mutations. Investigating the presence of additional mendelian mutations or risk variants in C9orf72 will be crucial in the understanding of the pathomechanism and to provide better diagnostic guidelines for molecular genetic testing and counseling. Since C9orf72 is the first gene causing FTLD-ALS, the characterization of this gene will be very important in the understanding of the common disease pathways." @default.
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- W2014034634 date "2012-07-01" @default.
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- W2014034634 title "P4-142: Genomic characterization of the C9orf72 promoter repeat in FTLD and ALS patients" @default.
- W2014034634 doi "https://doi.org/10.1016/j.jalz.2012.05.1845" @default.
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