Nancy D. Merner, Simon L. Girard, Hélène Catoire, Cynthia V

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Exome Sequencing Identifies FUS Mutations as a Cause of Essential Tremor Nancy D. Merner, Simon L. Girard, Hélène Catoire, Cynthia V. Bourassa, Véronique.

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Exome Sequencing Identifies FUS Mutations as a Cause of Essential Tremor Nancy D. Merner, Simon L. Girard, Hélène Catoire, Cynthia V. Bourassa, Véronique V. Belzil, Jean-Baptiste Rivière, Pascale Hince, Annie Levert, Alexandre Dionne-Laporte, Dan Spiegelman, Anne Noreau, Sabrina Diab, Anna Szuto, Hélène Fournier, John Raelson, Majid Belouchi, Michel Panisset, Patrick Cossette, Nicolas Dupré, Geneviève Bernard, Sylvain Chouinard, Patrick A. Dion, Guy A. Rouleau The American Journal of Human Genetics Volume 91, Issue 2, Pages 313-319 (August 2012) DOI: 10.1016/j.ajhg.2012.07.002 Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 1 A Schematic of ET Variants within FUS The American Journal of Human Genetics 2012 91, 313-319DOI: (10.1016/j.ajhg.2012.07.002) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 2 Expression of FUS mRNA Carrying ET and ALS Mutations (A) Lymphoblastoid cells derived from five ET-affected individuals (individuals II:13, III:14, IV:6, IV:11, and IV:12 in Figure S1) who carry the FUS c.868C>T (p.Gln290∗) mutation and from ALS-affected individuals expressing three different FUS mutations (c.1555C>T [p.Gln519∗], c.1562G>A [p.Arg521His], and c.1542-2A>C) were treated with the protein-synthesis inhibitor puromycin (300 μg for 6 hr). After this, treated cells were harvested, and total RNA was prepared (Trizol extraction, Invitrogen) alongside the total RNA of untreated cells. Quantitative RT-PCR reactions were then performed with a Taqman probe specific to FUS (∗∗∗p value = 6.47 × 10−5 [comparing the difference in mRNA expression in ET and ALS untreated cells]; ∗∗p value = 0.03 [comparing the difference in mRNA expression in ET and ALS treated cells]). For each group of affected (ET and ALS) individuals, the average levels of expression are plotted. t tests were used for statistics, and error bars correspond to the standard error of the mean (SEM). (B) Standard nonquantitative RT-PCR reactions were prepared with the RNA used in (A) and primers in the flanking exons (or UTRs) of each mutation. Amplified cDNA was sequenced, and whereas the ALS mutations were seen independently of a puromycin treatment, the ET mutation could only be seen in puromycin-treated cells. (C) Quantitative allele-specific expression measurements of the same five FUS c.868C>T ET individuals from above were made with a set of Taqman custom-designed probes and primers for the wild-type (c.868C) and mutant (c.868T) alleles. After the puromycin treatment, the expression of the mutant allele became detectable. The specificity of the custom probe for the c.868C>T transcript is demonstrated in Figure S5. All expression levels were normalized with the human 18S ribosomal RNA (rRNA) gene and were calculated in comparison to the average level of expression of two healthy controls. t tests were used for statistics, and error bars correspond to SEM. The American Journal of Human Genetics 2012 91, 313-319DOI: (10.1016/j.ajhg.2012.07.002) Copyright © 2012 The American Society of Human Genetics Terms and Conditions