Jump from Pre-mutation to Pathologic Expansion in C9orf72

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Jump from Pre-mutation to Pathologic Expansion in C9orf72 Zhengrui Xi, Marka van Blitterswijk, Ming Zhang, Philip McGoldrick, Jesse R. McLean, Yana Yunusova, Erin Knock, Danielle Moreno, Christine Sato, Paul M. McKeever, Raphael Schneider, Julia Keith, Nicolae Petrescu, Paul Fraser, Maria Carmela Tartaglia, Matthew C. Baker, Neill R. Graff-Radford, Kevin B. Boylan, Dennis W. Dickson, Ian R. Mackenzie, Rosa Rademakers, Janice Robertson, Lorne Zinman, Ekaterina Rogaeva The American Journal of Human Genetics Volume 96, Issue 6, Pages 962-970 (June 2015) DOI: 10.1016/j.ajhg.2015.04.016 Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigree of Family PED25 Individual ID and C9orf72 genotype are shown beneath the corresponding diamond. Arabic numbers indicate the repeat number, and “exp” represents the expansion allele. The age at time of examination is shown in the upper right corner. The age of death is indicated by a prefix of “d.” The age of onset is indicated for individuals with disease above the ID number. For protecting confidentiality, the gender of family members is masked. The results of methylation analyses for the 5′ CpG island and for (G4C2)n methylation are shown beneath the C9orf72 genotype. “Yes” represents the presence of methylation, and “no” represents the absence of methylation. The American Journal of Human Genetics 2015 96, 962-970DOI: (10.1016/j.ajhg.2015.04.016) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 2 Results of C9orf72 Genotyping PCR products of amplicon-length analysis and rp-PCR were separated on an ABI3100 DNA Analyzer and visualized by GeneScan software. Although five family members were identified to have expansions in the rp-PCR, only individual 9686 had a small expansion of ∼70 repeats. The American Journal of Human Genetics 2015 96, 962-970DOI: (10.1016/j.ajhg.2015.04.016) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 3 Southern Blot Results from Members of Family PED25 Southern blot analysis using blood DNA confirmed the presence of a small expansion in 9686 (highlighted by the red star), the presence of large expansions in 9698, 9707, and 9548, and the absence of an expansion in 9685 and 9697. The molecular-weight marker is shown on the left side of the Southern blot. “POS CON” and “NEG CON” refer to positive and negative control individuals, respectively. The American Journal of Human Genetics 2015 96, 962-970DOI: (10.1016/j.ajhg.2015.04.016) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 4 Southern Blot Results from Autopsy Tissues of Individual 9548 Southern blot analysis using genomic DNA extracted from autopsy tissues confirmed the presence of large expansions in CNS and non-CNS tissues from individual 9548. The American Journal of Human Genetics 2015 96, 962-970DOI: (10.1016/j.ajhg.2015.04.016) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 5 Chromatograms of the (G4C2)n-Methylation Assay in Blood Samples from Family PED25 Methylated and unmethylated G4C2-repeat alleles were detected by a methylation channel and a non-methylation channel, respectively. Detectable repeat size was marked along with the corresponding peak. The American Journal of Human Genetics 2015 96, 962-970DOI: (10.1016/j.ajhg.2015.04.016) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 6 Relative Quantification of C9orf72 mRNA in Blood and Fibroblast Samples from Family PED25 Both blood and fibroblasts of individuals with expansions (9548, 9698, and 9707) were tested. We also tested blood of individuals with normal alleles (9685 and 9697), as well as fibroblasts of 9697 and two normal control individuals. The relative quantity of each sample was scaled to that of individual 9676. Error bars represent the SE of the triplicate reactions. The American Journal of Human Genetics 2015 96, 962-970DOI: (10.1016/j.ajhg.2015.04.016) Copyright © 2015 The American Society of Human Genetics Terms and Conditions