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Brain. 2016 April; 139(4): e22.
Published online 2015 December 30. doi:  10.1093/brain/awv368
PMCID: PMC5006225

Reply: High prevalence of CHCHD10 mutations in patients with frontotemporal dementia from China

Sir,

In 2014, we provided a genetic basis to support the conclusion that mitochondrial dysfunction can have a causative effect in motor neuron degeneration. We reported a large family with a mitochondrial myopathy associated with motor neuron disease and cognitive decline looking like frontotemporal dementia (FTD). Since the identification of the p.Ser59Leu mutation in the CHCHD10 gene in this family, more than a dozen publications have reported CHCHD10 variants in patient cohorts from different geographic origins. CHCHD10-related clinical spectrum is continuously expanding and includes FTD, familial or sporadic amyotrophic lateral sclerosis (ALS), FTD-ALS, late-onset spinal motor neuropathy and Charcot-Marie-Tooth disease type 2 (Bannwarth et al., 2014; Chaussenot et al., 2014; Johnson et al., 2014; Müller et al., 2014; Auranen et al., 2015; Chiò et al., 2015; Dols-Icardo et al., 2015; Kurzwelly et al., 2015; Penttilä et al., 2015; Ronchi et al., 2015; Zhang et al., 2015).

We read with interest the Letter to the Editor from Bin et al. (2016) suggesting that CHCHD10 is the most important gene linked to FTD in the Chinese population. Among a cohort of 165 patients with ALS and 65 patients with FTD, they identified five novel CHCHD10 variants in five individuals with pure FTD (7.7%). No variant was detected in the ALS population. The putative pathogenicity of these variants was based not only on their absence both in control subjects and in different databases, but also in the in silico predictions. Among the different variants reported in the published studies, these criteria led to the selection of ~15 of them which are probably deleterious (Table 1). However, they are clearly insufficient to confirm pathogenicity and help determine the actual frequency of CHCHD10 mutations in the FTD-ALS clinical spectrum. Several studies have recently questioned the pathogenicity of the p.Pro34Ser substitution (Abdelkarim et al., 2015; Dobson-Stone et al., 2015; Dols-Icardo et al., 2015; Marroquin et al., 2015; Wong et al., 2015; Zhang et al., 2015). The p.Pro34Ser variant was found neither in ALS nor in FTD Chinese cohorts reported by Bin and colleagues but it is one that has been most commonly found in Caucasian populations. The observations that raise deservedly the question about its deleterious effect are (i) its identification in one FTD patient who carries a deleterious mutation in another FTD gene (Dobson-Stone et al., 2015); (ii) a non-segregation with the disease in a FTD family with only one of the two affected sisters of the index case carrying the p.P34S variant (Dobson-Stone et al., 2015); and (iii) its presence in non-affected subjects recently reported by several groups (Abdelkarim et al., 2015; Dobson-Stone et al., 2015; Dols-Icardo et al., 2015; Marroquin et al., 2015; Wong et al., 2015; Zhang et al., 2015). None of these results allow us to formally eliminate the deleterious role of this variant in the FTD-ALS clinical spectrum. Indeed, several studies have reported double mutations in ALS- or FTD-associated genes, suggesting an oligogenic model (van Blitterswijk et al., 2012, 2013; King et al., 2013) and it is possible that the Pro34Ser-negative patient in the FTD family reported by Dobson-Stone and colleagues (2015) is a phenocopy. Regarding the recent publications reporting the detection of the p.Pro34Ser variant in control populations, it should be noted that the late-onset of the disease can explain the detection of asymptomatic carriers who have not yet developed symptoms. Incomplete penetrance may also partly explain the presence of deleterious mutations in the general population and an incomplete penetrance in two families of German descent with ALS carrying the p.Arg15Leu mutation in CHCHD10 has been reported by Müller and colleagues (2014). C9orf72 expansions responsible for ALS and FTD have also been identified in control individuals with several studies reporting incomplete penetrance (van Blitterswijk et al., 2012).

Table 1
Potentially deleterious CHCHD10 variants

Functional tests are needed to elucidate the role of the variants identified in clinical studies. We do not have fibroblasts from patients carrying the p.Pro34Ser substitution. We therefore expressed the CHCHD10P34S mutant allele in HeLa cells and compared the effects of the mutation to those observed with the CHCHD10S59L mutant. The pathogenicity of the p.Ser59Leu mutation is clearly demonstrated and mainly based on its co-segregation with the disease in a large family and on the mitochondrial dysfunction observed both in patient fibroblasts and in HeLa cells overexpressing the mutant allele (Table 1) (Bannwarth et al., 2014). Overexpression of mutant CHCHD10P34S led to a significant fragmentation of the mitochondrial network contrary to overexpression of the wild-type allele. Electron microscopy confirmed that CHCHD10P34S expression alters mitochondrial morphology with loss and disorganization of mitochondrial cristae. Furthermore, the expression of either CHCHD10S59L or CHCHD10P34S mutant has the same deleterious effects on nucleoid organization and apoptosis (Genin et al., 2016). These results are strikingly similar to those observed both in fibroblasts of patients carrying the p.Ser59Leu mutation and in HeLa cells overexpressing the CHCHD10S59L mutant allele. They confirm the pathogenic effect of the p.Pro34Ser mutation.

The identification of variants in disease-associated genes has significant implications for the determination of frequency of pathogenic variants but also for genetic diagnostics and counselling. Our results show the difficulty in confirming the pathogenicity of a variant in the absence of functional studies particularly in late-onset dominant diseases with incomplete penetrance. Zhang and colleagues (2015) also identified the p.Pro34Ser mutation in one individual with Parkinson’s disease and two patients with Alzheimer’s disease, suggesting that the clinical spectrum of CHCH10 may be extended to other neurodegenerative diseases.

Funding

This work was made possible by grants to V.P-F. from the Association Française contre les Myopathies (AFM) and the Fondation pour la Recherche Médicale (FRM), to H.S. from National Institutes of Health (GM089853) and to A.B. by the program “Investissements d’avenir” ANR-10-IAIHU-06, ‘The Programme Hospitalier de Recherche Clinique’ (to I.L.B.) and the 7th framework program of the European Union (FP7, E12009DD, Neuromics). P.Y.W.M. is supported by a Clinician Scientist Fellowship Award (G1002570) from the Medical Research Council (UK). P.Y.W.M. also receives funding from Fight for Sight (UK) and the UK National Institute of Health Research (NIHR) as part of the Rare Diseases Translational Research Collaboration.

References

  • Abdelkarim S, Morgan S, Plagnol V, Lu CH, Adamson G, Howard R, et al. CHCHD10 Pro34Ser is not a highly penetrant pathogenic variant for amyotrophic lateral sclerosis and frontotemporal dementia. Brain 2015. Advance Access published on September 11, 2015, doi: 10.1093/brain/awv223. [PubMed]
  • Ajroud-Driss S, Fecto F, Ajroud K, Lalani I, Calvo SE, Mootha VK, et al. Mutation in the novel nuclear-encoded mitochondrial protein CHCHD10 in a family with autosomal dominant mitochondrial myopathy. Neurogenetics 2015; 16: 1–9. [PMC free article] [PubMed]
  • Auranen M, Ylikallio E, Shcherbii M, Paetau A, Kiuru-Enari S, Toppila JP, et al. CHCHD10 variant p.(Gly66Val) causes axonal Charcot-Marie-Tooth disease. Neurol Genet 2015; 1: e1. [PMC free article] [PubMed]
  • Bannwarth S, Ait-El-Mkadem S, Chaussenot A, Genin EC, Lacas-Gervais S, Fragaki K, et al. A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement. Brain 2014; 137: 2329–45. [PMC free article] [PubMed]
  • Bin J, Tingting X, Lihua H, Xiaohua G, Lin Z, et al. High prevalence of CHCHD10 mutation in patients with frontotemporal dementia from China. Brain 2016; 139: e21. [PubMed]
  • Chaussenot A, Le Ber I, Ait-El-Mkadem S, Camuzat A, de Septenville A, Bannwarth S, et al. Screening of CHCHD10 in a French cohort confirms the involvement of this gene in frontotemporal dementia with amyotrophic lateral sclerosis patients. Neurobiol Aging 2014; 35: 2884.e1–4. [PubMed]
  • Chiò A, Mora G, Sabatelli M, Caponnetto C, Traynor BJ, Johnson JO, et al. CHCH10 mutations in an Italian cohort of familial and sporadic amyotrophic lateral sclerosis patients. Neurobiol Aging 2015; 36: 1767.e3–6. doi: 10.1016/j.neurobiolaging.2015.01.017. [PMC free article] [PubMed]
  • Dobson-Stone C, Shaw AE, Hallupp M, Bartley M, McCann H, Brooks WS, et al. Is CHCHD10 Pro34Ser pathogenic for frontotemporal dementia and amyotrophic lateral sclerosis ? Brain 2015; 138: e385. [PubMed]
  • Dols-Icardo O, Nebot I, Gorostidi A, Ortega-Cubero S, Hernández I, Rojas-García R, et al. Analysis of the CHCHD10 gene in patients with frontotemporal dementia and amyotrophic lateral sclerosis from Spain. Brain 2015; 138: e400. [PubMed]
  • Genin EC, Plutino M, Bannwarth S, Villa E, Cisneros-Barroso E, Roy M, et al. EMBO Mol Med; 2016, in press.
  • Johnson JO, Glynn SM, Gibbs JR, Nalls MA, Sabatelli M, Restagno G, et al. Mutations in the CHCHD10 gene are a common cause of familial amyotrophic lateral sclerosis. Brain 2014; 137: e311. [PMC free article] [PubMed]
  • King A, Al-Sarraj S, Troakes C, Smith BN, Maekawa S, Iovino M, et al. Mixed tau, TDP-43 and p62 pathology in FTLD associated with a C9ORF72 repeat expansion and p.Ala239Thr MAPT (tau) variant. Acta Neuropathol 2013; 125: 303–10. [PubMed]
  • Kurzwelly D, Krüger S, Biskup S, Heneka MT. A distinct clinical phenotype in a German kindred with motor neuron disease carrying a CHCHD10 mutation. Brain 2015; 138: e376. [PubMed]
  • Marroquin N, Stranz S, Müller K, Wieland T, Ruf WP, Brockmann SJ, et al. Screening for CHCHD10 mutations in a large cohort of sporadic ALS patients: no evidence for pathogenicity of the p.P34S variant. Brain 2015. Advance Access published on September 11, 2015. [PubMed]
  • Müller K, Andersen PM, Hübers A, Marroquin N, Volk AE, Danzer KM, et al. Two novel mutations in conserved codons indicate that CHCHD10 is a gene associated with motor neuron disease. Brain 2014; 137: e309. [PubMed]
  • Pasanen P, Myllykangas L, Pöyhönen M, Kiuru-Enari S, Tienari PJ, Laaksovirta H, et al. Intrafamilial clinical variability in individuals carrying the CHCHD10 mutation Gly66Val. Acta Neurol Scand 2015. Advance Access published on July 30, 2015, doi: 10.1111/ane.12470. [PubMed]
  • Penttilä S, Jokela M, Bouquin H, Saukkonen AM, Toivanen J, Udd B. Late onset spinal motor neuronopathy is caused by mutation in CHCHD10. Ann Neurol 2015; 77: 163–72. [PubMed]
  • Ronchi D, Riboldi G, Del Bo R, Ticozzi N, Scarlato M, Galimberti D, et al. CHCHD10 mutations in Italian patients with sporadic amyotrophic lateral sclerosis. Brain 2015; 138: e372. [PubMed]
  • van Blitterswijk M, Baker MC, DeJesus-Hernandez M, Ghidoni R, Benussi L, Finger E, et al. C9ORF72 repeat expansions in cases with previously identified pathogenic mutations. Neurology 2013; 81: 1332–41. [PMC free article] [PubMed]
  • van Blitterswijk M, van Es MA, Hennekam EA, Dooijes D, van Rheenen W, Medic J, et al. Evidence for an oligogenic basis of amyotrophic lateral sclerosis. Hum Mol Genet 2012; 21: 3776–84. [PubMed]
  • Wong CH, Topp S, Gkazi AS, Troakes C, Miller JW, de Majo M, et al. The CHCHD10 P34S variant is not associated with ALS in a UK cohort of familial and sporadic patients. Neurobiol Aging 2015; 36: 2908.e17–8. [PubMed]
  • Zhang M, Xi Z, Zinman L, Bruni AC, Maletta RG, Curcio SA, et al. Mutation analysis of CHCHD10 in different neurodegenerative diseases. Brain 2015; 138:e380 doi: 10.1093/brain/awv082. [PMC free article] [PubMed]

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