Investigating the role of ALS genes CHCHD10 and TUBA4A in Belgian FTD-ALS spectrum patients Federica Perrone, Hung Phuoc Nguyen, Sara Van Mossevelde,

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Investigating the role of ALS genes CHCHD10 and TUBA4A in Belgian FTD-ALS spectrum patients Federica Perrone, Hung Phuoc Nguyen, Sara Van Mossevelde, Matthieu Moisse, Anne Sieben, Patrick Santens, Jan De Bleecker, Mathieu Vandenbulcke, Sebastiaan Engelborghs, Jonathan Baets, Patrick Cras, Rik Vandenberghe, Peter De Jonghe, Peter P. De Deyn, Jean-Jacques Martin, Philip Van Damme, Christine Van Broeckhoven, Julie van der Zee Dirk Nuytten, Katrien Smets, Jan Versijpt, Alex Michotte, Adrian Ivanoiu, Olivier Deryck, Bruno Bergmans, Jean Delbeck, Marc Bruyland, Christiana Willems, Eric Salmon Federica Perrone, Hung Phuoc Nguyen, Sara Van Mossevelde, Matthieu Moisse, Anne Sieben, Patrick Santens, Jan De Bleecker, Mathieu Vandenbulcke, Sebastiaan Engelborghs, Jonathan Baets, Patrick Cras, Rik Vandenberghe, Peter De Jonghe, Peter P. De Deyn, Jean- Jacques Martin, Philip Van Damme, Christine Van Broeckhoven, Julie van der Zee Dirk Nuytten, Katrien Smets, Jan Versijpt, Alex Michotte, Adrian Ivanoiu, Olivier Deryck, Bruno Bergmans, Jean Delbeck, Marc Bruyland, Christiana Willems, Eric Salmon Neurobiology of Aging Volume 51, Pages 177.e9-177.e16 (March 2017) DOI: 10.1016/j.neurobiolaging.2016.12.008 Copyright © 2017 The Authors Terms and Conditions

Fig. 1 Schematic representation of the CHCHD10 and TUBA4A protein structure with identified and reported mutations. (A) Predicted structural and functional domains of CHCHD10 with identified coding variations (NM_213720.2) in the present study (top) and reported variations (bottom). Mitochondrial targeting sequence (1–16), hydrophobic helix (43–68), coiled helix coiled helix (CHCH) domain (twin CX9C; 102–133) (Cozzolino et al., 2015) are indicated. Coding variants in FTD patients are in red, in ALS patients in green, in FTD/ALS patients in orange, and in mitochondrial myopathy patients in black. Variants that were found in both patients and control individuals are in gray. Listed coding variants in CHCHD10 are reported by the present study and by Ajroud-Driss et al. (2015), Bannwarth et al. (2014), Chaussenot et al. (2014), Dols-Icardo et al. (2015), Jiao et al. (2016), Johnson et al. (2014), Kurzwelly et al. (2015), Muller et al. (2014), Ronchi et al. (2015), Teyssou et al. (2016) and Zhang et al. (2015). (B) The TUBA4A protein with identified coding variations (NM_006000.2) in the present study (top) and reported variations (bottom, Pensato et al., 2015; Smith et al., 2014). The color scheme of the variants is similar to that of panel A. aThis variant was found in an index patient with a C9orf72 repeat expansion mutation. Neurobiology of Aging 2017 51, 177.e9-177.e16DOI: (10.1016/j.neurobiolaging.2016.12.008) Copyright © 2017 The Authors Terms and Conditions

Fig. 2 Expression of the mutant transcripts in lymphoblast cell lines of PTC mutation carriers. Presence or absence of the mutation on gDNA extracted from blood and cDNA prepared from lymphoblast cell lines of the carrier of the CHCHD10 c.322C>T (p.Gln108*) mutation (A) and of the TUBA4A c.187del (p.Arg64Glyfs*90) mutation (B) showing loss of the mutant transcript for the CHCHD10 p.Gln108* mutation predicting a null allele and presence of the mutated frameshift transcript for the p.Arg64Glyfs*90 mutation predicting translation of a truncated protein. The CHCHD10 and TUBA4A genes are both transcribed from the antisense strand, as such the G>A substitution as shown on the trace file is complementary to the CHCHD10 c.322C>T substitution on the sense strand of the reference genome (Human GRCh38/hg38). Abbreviations: cDNA, complementary DNA; gDNA, genomic DNA; PTC, premature termination codon. Neurobiology of Aging 2017 51, 177.e9-177.e16DOI: (10.1016/j.neurobiolaging.2016.12.008) Copyright © 2017 The Authors Terms and Conditions