Screening for<i>CHCHD10</i>mutations in a large cohort of sporadic ALS patients: no evidence for pathogenicity of the p.P34S variant: Table 1

Marroquin, Nicolai; Stranz, Sebastian; Müller, Kathrin; Wieland, Thomas; Ruf, Wolfgang; Brockmann, Sarah J; Danzer, Karin M; Borck, Guntram; Hübers, Annemarie; Weydt, Patrick; Meitinger, Thomas; Strom, Tim-Matthias; Rosenbohm, Angela; Ludolph, Albert C.; Weishaupt, Jochen H.

doi:10.1093/brain/awv218

Cited by 21 publications

(23 citation statements)

References 9 publications

(38 reference statements)

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“…Despite efforts to elucidate their pathogenic mechanisms, many controversial findings suggest that mutations in CHCHD10 do not share a common disease-causing mechanism (1,11,12,(19)(20)(21)(22)25). Our results also mirror these current controversial findings.…”

Section: Discussionsupporting

confidence: 86%

“…The CHCHD10 P34S variant occurs in sporadic ALS (8,9), ALS-FTD (10), Parkinson disease (6), and Alzheimer disease (6), and its overexpression causes mitochondrial defects (11). However, its pathogenicity is not well supported by genetic evidence (12,13). CHCHD10 G58R and CHCHD10 G66V were identified in mitochondrial myopathy and late-onset spinal muscular atrophy, jokela type (SMAJ) or Charcot-Marie-Tooth disease type 2 (CMT2), respectively (5,(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

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Dominant toxicity of ALS–FTD-associated CHCHD10^S59L is mediated by TDP-43 and PINK1

Baek

Choe

Dorn³

et al. 2019

Preprint

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†Authors contributed equally.One Sentence Summary: Inhibition of TDP-43 mitochondrial translocation or PINK1 kinase activity mitigates CHCHD10 S59L -mediated mitochondrial toxicity. AbstractMutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) are a genetic cause of amyotrophic lateral sclerosis and/or frontotemporal dementia (ALS-FTD). To elucidate how mutations in CHCHD10 induce disease, we generated a Drosophila melanogaster model of CHCHD10-mediated ALS-FTD. Expression of CHCHD10 S59L in Drosophila caused gain-offunction toxicity in eyes, motor neurons, and muscles, in addition to mitochondrial defects in flies and HeLa cells. TDP-43 and PINK1 formed two axes, driving the mutant-dependent phenotypes. CHCHD10 S59L expression increased TDP-43 insolubility and mitochondrial translocation. Blocking mitochondrial translocation with a peptide inhibitor reduced CHCHD10 S59L -mediated toxicity. PINK1 knockdown rescued CHCHD10 S59L -mediated phenotypes in Drosophila and HeLa cells. The two PINK1 substrates mitofusin and mitofilin were genetic modifiers of this phenotype. Mitofusin agonists reversed the CHCHD10 S59Linduced phenotypes in Drosophila and HeLa cells and increased ATP production in Drosophila expressing C9orf72 with expanded GGGGCC repeats. Two peptides inhibitors of PINK1 mitigated the mitochondrial defects introduced by CHCHD10 S59L expression. These findings indicate that TDP-43 mitochondrial translocation and chronic activation of PINK1-mediated pathways by CHCHD10 S59L generate dominant toxicity. Therefore, inhibiting PINK1 activity may provide a therapeutic strategy for CHCHD10-associated disease.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Dominant toxicity of ALS–FTD-associated CHCHD10^S59L is mediated by TDP-43 and PINK1

Baek

Choe

Dorn³

et al. 2019

Preprint

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“…); however, without segregation in families the pathogenicity of each of the reported variants is not known and especially the p.P34S mutation which has also been observed in controls is regarded by many groups as a polymorphism (Marroquin et al . ; Wong et al . ).…”

Section: Rare Ftld Disease Genesmentioning

confidence: 99%

“…The first pathogenic mutation in the coiled-coil-helix-coiledcoil-helix domain containing 10 (CHCHD10) gene, p.S59L, was identified by exome sequencing in an atypical family with late-onset motor neuron disease, cognitive decline resembling bvFTD, cerebellar ataxia, and mitochondrial myopathy (Bannwarth et al 2014). Follow-up studies in FTLD and ALS patients of mostly European descent identified additional potential pathogenic mutations in 1-3% of patients Johnson et al 2014;Dols-Icardo et al 2015;Zhang et al 2015); however, without segregation in families the pathogenicity of each of the reported variants is not known and especially the p.P34S mutation which has also been observed in controls is regarded by many groups as a polymorphism (Marroquin et al 2015;Wong et al 2015). Interestingly, a recent study in Asian FTLD and ALS patients identified CHCHD10 mutations in 5 out of 67 FTLD patients (7.7%), whereas mutations in MAPT, GRN, and C9orf72 were each responsible for < 3% of FTLD patients in the same population, suggesting CHCHD10 is the most common FTLD gene in Asia (Jiao et al 2015).…”

Section: Chchd10mentioning

confidence: 99%

Genetics of FTLD: overview and what else we can expect from genetic studies

Pottier

Ravenscroft

Sanchez‐Contreras

et al. 2016

Journal of Neurochemistry

130

119

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Frontotemporal lobar degeneration (FTLD) comprises a highly heterogeneous group of disorders clinically associated with behavioral and personality changes, language impairment, and deficits in executive functioning, and pathologically associated with degeneration of frontal and temporal lobes. Some patients present with motor symptoms including amyotrophic lateral sclerosis. Genetic research over the past two decades in FTLD families led to the identification of three common FTLD genes (microtubule-associated protein tau, progranulin, and chromosome 9 open reading frame 72) and a small number of rare FTLD genes, explaining the disease in almost all autosomal dominant FTLD families but only a minority of apparently sporadic patients or patients in whom the family history is less clear. Identification of additional FTLD (risk) genes is therefore highly anticipated, especially with the emerging use of next-generation sequencing. (FUS, EWS, TAF15); MAPT, microtubule-associated tau gene; CBD, corticobasal degeneration; PSP, progressive supranuclear palsy; GGT, globular glial tauopathies; AGD, argyrophilic grain disease; AD, Alzheimer's disease; TDP-43, TAR DNA-binding protein; FUS, fused in sarcoma; aFTLD-U, atypical-FTLD-U; EWS, ewing in sarcoma; TAF15, TATA-binding protein-associated factor 15; FTDP-17, frontotemporal dementia and parkinsonism linked to chromosome 17; cM, centimorgan; PiD, Pick's disease; MT, microtubule; NFTs, neurofibrillary tangles; iPSC, induced pluripotent stem cells; GRN, progranulin; CSF, cerebrospinal fluid; CBS, corticobasal syndrome; NCL, neuronal ceroid lipofuscinosis; SAHA, suberoylanilide hydroxamic acid; C9orf72, chromosome 9 open reading frame 72; DPRs, dipeptide repeat proteins; DENN, differentially expressed in normal and neoplasia; GEF, guanine nucleotide exchange factors; CHMP2B, charged multivesicular body protein 2B; ESCRT-III, endosome sorting complex required for transport 3; VCP, valosin-containing protein gene; IBM, inclusion body myopathy; PDB, paget disease of the bone; IBMPFD, inclusion body myopathy with Paget disease of the bone and frontotemporal dementia; MSP, multisystem proteinopathy; hnRNPA1, heterogeneous nuclear ribonucleoprotein A1; hnRNPA2B1, heterogeneous nuclear ribonucleoprotein A2/B1; SQSTM1, sequestosome 1; TBK1, TANK binding kinase 1; OPTN, optineurin; TRN1, transportin; CHCHD10, coiled-coil-helix-coiled-coil-helix domain containing 10; MICOS, mitochondrial contact site and cristae organization system; UBQLN2, ubiquilin 2; DCTN1, dynactin 1; CSF1R, colony stimulating receptor factor 1 gene; PRKAR1B, protein kinase A type I-beta regulatory subunit gene; TREM2, triggering receptor expressed on myeloid cells 2 gene; TMEM106B, the transmembrane protein 106B gene; GWAS, genome-wide association study; SNP, single nucleotide polymorphism; CTSC, cathepsin C; ATXN2, ataxin 2 gene; APOE, apolipoprotein E; PRNP, prion protein and UNC13A unc-13 homolog A, C. elegans; ANG, angiogenin; GENFI, genetic and frontotemporal dementia initiative; LEFFTDS, Longitudi...

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“…27 pathogenicity of this variant in pure ALS ± FTD, our data add to the increasing evidence that the p.Pro34Ser mutation in CHCHD10 is probably not pathogenic. [21][22][23][24] Recent in vitro studies still support p.Pro34Ser pathogenicity, as similar cellular pathology between CHCHD10 S59L and CHCHD10 P34S mutant cell lines was shown. 25 Despite the in vitro findings, that the p.Pro34Ser variant is as common in ALS patients as in the general population indicates that an apparently abnormal phenotype in transfected cell lines alone does not justify classifying the p.Pro34Ser variant as an ALS-causing mutation and indicates the substantial limitation of these models to represent human ALS pathology.…”

Section: Discussionmentioning

confidence: 99%

CHCHD10 variants in amyotrophic lateral sclerosis: Where is the evidence?

2018

Annals of Neurology

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CHCHD10 mutations seem to be a far less prevalent cause of pure ALS than previously suggested, and instead appear related to more complex phenotypes. There appears to be insufficient evidence for the pathogenicity of most previously reported variants in pure ALS. This study shows that routine testing for CHCHD10 mutations in pure ALS is not recommended and illustrates the importance of sufficient genetic and functional evidence in establishing pathogenicity of genetic variants. Ann Neurol 2018;83:110-116.

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Screening forCHCHD10mutations in a large cohort of sporadic ALS patients: no evidence for pathogenicity of the p.P34S variant: Table 1

Cited by 21 publications

References 9 publications

Dominant toxicity of ALS–FTD-associated CHCHD10^S59L is mediated by TDP-43 and PINK1

Dominant toxicity of ALS–FTD-associated CHCHD10^S59L is mediated by TDP-43 and PINK1

Genetics of FTLD: overview and what else we can expect from genetic studies

CHCHD10 variants in amyotrophic lateral sclerosis: Where is the evidence?

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Screening forCHCHD10mutations in a large cohort of sporadic ALS patients: no evidence for pathogenicity of the p.P34S variant: Table 1

Cited by 21 publications

References 9 publications

Dominant toxicity of ALS–FTD-associated CHCHD10S59L is mediated by TDP-43 and PINK1

Dominant toxicity of ALS–FTD-associated CHCHD10S59L is mediated by TDP-43 and PINK1

Genetics of FTLD: overview and what else we can expect from genetic studies

CHCHD10 variants in amyotrophic lateral sclerosis: Where is the evidence?

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Dominant toxicity of ALS–FTD-associated CHCHD10^S59L is mediated by TDP-43 and PINK1

Dominant toxicity of ALS–FTD-associated CHCHD10^S59L is mediated by TDP-43 and PINK1