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Screening for CHCHD10 mutations in a large cohort of sporadic ALS patients: no evidence for pathogenicity of the p.P34S variant

Nicolai Marroquin, Sebastian Stranz, Kathrin Müller, Thomas Wieland, Wolfgang P. Ruf, Sarah J. Brockmann, Karin M. Danzer, Guntram Borck, Annemarie Hübers, Patrick Weydt, Thomas Meitinger, Tim-Matthias Strom, Angela Rosenbohm, Albert C. Ludolph, Jochen H. Weishaupt
DOI: http://dx.doi.org/10.1093/brain/awv218 e8 First published online: 11 September 2015


Bannwarth et al. (2014) reported a mutation in CHCHD10 responsible for a variable phenotype including cerebellar ataxia, hearing impairment, myopathy, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This gene encodes the coiled-coil helix coiled-coil helix domain-containing protein 10 of largely unknown function. It is a strictly mitochondrially located protein that may be involved in respiratory chain function or mitochondrial genome stability (Bannwarth et al., 2014). Several subsequent publications provided further evidence that CHCHD10 mutations can cause familial motor neuron disease/ALS (familial ALS), with an unusually slow disease progression in most patients (Bannwarth et al., 2014; Johnson et al., 2014; Müller et al., 2014; Kurzwelly et al., 2015; Penttila et al., 2015). As an important argument for CHCHD10 causing ALS, co-segregation with disease could be demonstrated for the three CHCHD10 variants p.R15L (Johnson et al., 2014; Müller et al., 2014; Kurzwelly et al., 2015), p.S59L (Bannwarth et al., 2014) and p.G66V (Penttila et al., 2015). The strongest genetic evidence for causality exists with regard to the p.G66V mutation, which was first detected by Müller et al. (2014) in a single patient with familial ALS and subsequently shown to co-segregate with a slowly progressing motor neuron disease in a total of 17 pedigrees (Penttila et al., 2015). Hence there is meanwhile unequivocal evidence that CHCHD10 mutation can cause familial motor neuron degeneration. No association of CHCHD10 variants with ALS could be shown in genome-wide association studies, which can plausibly be explained by the low frequency of CHCHD10 mutations in familial ALS patient cohorts (Bannwarth et al., 2014; Johnson et al., 2014; Müller et al., 2014). Consequently, due to the …

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