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Sylvie Bannwarth, Samira Ait-El-Mkadem, Annabelle Chaussenot, Emmanuelle C. Genin, Sandra Lacas-Gervais, Konstantina Fragaki, Laetitia Berg-Alonso, Yusuke Kageyama, Valérie Serre, David Moore, Annie Verschueren, Cécile Rouzier, Isabelle Le Ber, Gaëlle Augé, Charlotte Cochaud, Françoise Lespinasse, Karine N’Guyen, Anne de Septenville, Alexis Brice, Patrick Yu-Wai-Man, Hiromi Sesaki, Jean Pouget, Véronique Paquis-Flucklinger, Reply: Two novel mutations in conserved codons indicate that CHCHD10 is a gene associated with motor neuron disease, Brain, Volume 137, Issue 12, December 2014, Page e310, https://doi.org/10.1093/brain/awu228
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Sir,
In a recent publication in Brain, we described a novel heterozygous CHCHD10 mutation (c.176C>T; p.Ser59Leu) in a large French family with a late-onset phenotype including cognitive decline resembling frontotemporal dementia (FTD), motor neuron disease, cerebellar ataxia and mitochondrial myopathy with multiple mtDNA deletions (Bannwarth et al., 2014). We found the same pathogenic mutation in one family in a cohort of 21 families with pathologically proven FTD-ALS (amyotrophic lateral sclerosis). We also showed that the CHCHD10 gene encodes a mitochondrial protein located in the intermembrane space, and that it is likely involved in the maintenance of cristae junctions and mtDNA stability. This work led to the identification of a novel gene responsible for FTD-ALS and the intriguing realization that mitochondrial dysfunction could be an important pathophysiological player contributing to the aetiology of these diseases.
The letter from Müller et al. (2014) contains important information that confirms the involvement of the CHCHD10 gene in ALS. They performed whole exome sequencing in 102 German and 26 Nordic ALS patients. By screening CHCHD10, they identified two novel heteozygous variants: c.44G>T (p.Arg15Leu) in two German families and c.197G>T (p.Gly66Val) in one Finnish family. Although it was not possible to confirm the deleterious nature of these variants through segregation analysis due to the limited number of DNA samples available per family, their absence in public and in-house SNP databases, and in ethnically matched controls in addition to the evolutionary conservation of the corresponding amino acid residues are all in favour of a pathogenic effect. The p.Arg15Leu substitution is located in a non-structured N-terminal region whereas the p.Gly66Val substitution is located in the hydrophobic N-terminal α-helix. The latter amino acid change is in close physical proximity to the c.176C>T (p.Ser59Leu) mutation that we previously reported in FTD-ALS, and might possibly destabilize the α-helix conformation with resulting altered protein-protein interactions (Banci et al., 2012; Bannwarth et al., 2014).
