Short Expansions May Predispose Offspring to ALS

The most common cause of familial ALS is the expansion of a non-coding hexanucleotide repeat in the C9ORF72 gene (see Sept 2011 news). But how many GGGGCC repeats are necessary to trigger the disease? According to a paper in the June 4 American Journal of Human Genetics, the key predictor may be methylation of the repeats, which shuts down C9ORF72 gene expression (see March 2015 news). Scientists led by Ekaterina Rogaeva and Lorne Zinman from the University of Toronto, Canada studied a family in which four of five adult siblings carried the expanded version of the gene. Two of them had developed ALS, yet none of their parents or grandparents had been afflicted. Interestingly, one of the father’s copies of the C9ORF72 gene contained 70 unmethylated repeats, which expanded in the offspring to a methylated, high copy repeat gene. These findings could provide a new allele to help predict predisposition to ALS.

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Xi Z, van Blitterswijk M, Zhang M, McGoldrick P, McLean JR, Yunusova Y, Knock E, Moreno D, Sato C, McKeever PM, Schneider R, Keith J,Petrescu N, Fraser P, Tartaglia MC, Baker MC, Graff-Radford NR, Boylan KB, Dickson DW, Mackenzie IR, Rademakers R, Robertson J, Zinman L, Rogaeva E. Jump from Pre-mutation to Pathologic Expansion in C9orf72. Am J Hum Genet. 2015 Jun 4;96(6):962-70. [Pubmed].

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