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Mutation analysis of CHCHD10 in different neurodegenerative diseases

2015; Oxford University Press; Volume: 138; Issue: 9 Linguagem: Inglês

10.1093/brain/awv082

1460-2156

Ming Zhang, Zhengrui Xi, Lorne Zinman, Amalia C. Bruni, Raffaele Maletta, Sabrina A.M. Curcio, Innocenzo Rainero, Elisa Rubino, Lorenzo Pinessi, Benedetta Nacmias, Sandro Sorbi, Daniela Galimberti, Anthony E. Lang, Susan H. Fox, Ezequiel Surace, Mahdi Ghani, Jing Guo, Christine Sato, Danielle Moreno, Yan Liang, Julia Keith, Bryan J. Traynor, Peter St George‐Hyslop, Ekaterina Rogaeva,

Genetic Neurodegenerative Diseases

Sir, A recent study by Bannwarth et al. (2014) implicated CHCHD10 as a novel gene for amyotrophic lateral sclerosis/frontotemporal lobar degeneration (ALS/FTLD), reporting a p.S59L substitution (c.176C > T; NM_213720.2) in a large French kindred. Affected family members were presented with a complex phenotype that included symptoms of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), cerebellar ataxia, Parkinson’s disease and a mitochondrial myopathy associated with multiple mitochondrial DNA deletions. So far, seven missense CHCHD10 mutations have been reported in patients with a broad phenotypic range, including ALS/FTLD (p.S59L and p.P34S) (Bannwarth et al. , 2014; Chaussenot et al. , 2014), ALS (p.R15L and p.G66V) (Johnson et al. , 2014; Muller et al. , 2014), myopathy (p.R15S and p.G58R) (Ajroud-Driss et al. , 2015) and late-onset spinal motor neuronopathy (p.G66V) (Penttila et al. , 2015). All of them affect exon 2 (a mutational hotspot of CHCHD10 ). Notably, mitochondrial dysfunction has been implicated in several neurodegenerative diseases (Lin and Beal, 2006; Cozzolino et al. , 2013); however, there are no studies evaluating the contribution of CHCHD10 to pure FTLD, Parkinson’s disease or Alzheimer’s disease. Hence, we sequenced CHCHD10 exon 2 in 204 ALS, 153 Parkinson’s disease and 141 Alzheimer’s disease patients from Canada and 158 FTLD patients from Italy in addition to 497 control subjects from USA/UK, Canada and Italy. The cases of ALS and FTLD were free from mutations in SOD1 , GRN , FUS , TARDBP and MATR3 or a repeat expansion in C9orf72 . We identified a known CHCHD10 pathogenic p.R15L mutation (Johnson et al. , 2014; Muller et al. , 2014) in a patient with sporadic ALS (Patient 8807) (Fig. 1A), who developed symptoms involving his upper limb at 54 years of age and remains alive 12 years later. The p.R15L …