Analysis of the<i>CHCHD10</i>gene in patients with frontotemporal dementia and amyotrophic lateral sclerosis from Spain

Dols‐Icardo, Oriol; Nebot, Irene; Gorostidi, Ana; Ortega‐Cubero, Sara; Hernández, Isabel; Rojas‐García, Ricard; García‐Redondo, Alberto; Povedano, Mònica; Lladó, Albert; Álvarez, Victoria; Sánchez‐Juan, Pascual; Pardo, Julio; Jericó, Ivonne; Vázquez-Costa, Juan Francisco; Sevilla, Teresa; Cardona, Fernando; Indakoechea, Begoña; Moreno, Fermín; Fernández‐Torrón, Roberto; Muñoz, Laia; Moreno‐Grau, Sonia; Rosende-Roca, Maiteé; Vela, A.; Muñoz-Blanco, José Luís; Combarros, Onofre; Coto, Eliécer; Alcolea, Daniel; Fortea, Juan; Lleó, Alberto; Sánchez‐Valle, Raquel; Esteban-Pérez, Jesús; Ruiz, Agustín; Pástor, Pau; Munáin, Adolfo López de; Pérez-Tur, Jordi; Clarimón, Jordi

doi:10.1093/brain/awv175

Cited by 58 publications

(40 citation statements)

References 9 publications

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“…To test, whether impaired mitochondrial import is a common pathomechanism, we examined steady state protein levels and localization of all reported missense CHCHD10 variants (Bannwarth et al , ; Ajroud‐Driss et al , ; Dols‐Icardo et al , ; Jiao et al , ; Perrone et al , ; Zhou et al , ). In public exome sequencing data from ~ 2,000 ALS patients (ALSdb, Cirulli et al , ), we discovered two additional CHCHD10 mutations in the CHCH domain that are rare in the ExAc database (Lek et al , ).…”

Section: Resultsmentioning

confidence: 99%

“…The typical age‐of‐onset in these families is in the fifties, and patients show variable clinical presentation and disease duration (1–12 years). Sequencing studies identified several other CHCHD10 mutations in ALS/FTD cohorts, but lack functional characterization to support pathogenicity (Chaussenot et al , ; Dols‐Icardo et al , ; Zhang et al , ; Jiao et al , ; Zhou et al , ; Blauwendraat et al , ).…”

Section: Introductionmentioning

confidence: 99%

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A novel CHCHD10 mutation implicates a Mia40‐dependent mitochondrial import deficit in ALS

et al. 2018

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CHCHD10 mutations are linked to amyotrophic lateral sclerosis, but their mode of action is unclear. In a 29‐year‐old patient with rapid disease progression, we discovered a novel mutation (Q108P) in a conserved residue within the coiled‐coil‐helix‐coiled‐coil‐helix (CHCH) domain. The aggressive clinical phenotype prompted us to probe its pathogenicity. Unlike the wild‐type protein, mitochondrial import of CHCHD10 Q108P was blocked nearly completely resulting in diffuse cytoplasmic localization and reduced stability. Other CHCHD10 variants reported in patients showed impaired mitochondrial import (C122R) or clustering within mitochondria (especially G66V and E127K) often associated with reduced expression. Truncation experiments suggest mitochondrial import of CHCHD10 is mediated by the CHCH domain rather than the proposed N‐terminal mitochondrial targeting signal. Knockdown of Mia40, which introduces disulfide bonds into CHCH domain proteins, blocked mitochondrial import of CHCHD10. Overexpression of Mia40 rescued mitochondrial import of CHCHD10 Q108P by enhancing disulfide‐bond formation. Since reduction in CHCHD10 inhibits respiration, mutations in its CHCH domain may cause aggressive disease by impairing mitochondrial import. Our data suggest Mia40 upregulation as a potential therapeutic salvage pathway.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A novel CHCHD10 mutation implicates a Mia40‐dependent mitochondrial import deficit in ALS

et al. 2018

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“…; Dols‐Icardo et al . ; Zhang et al . ); 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 .…”

Section: Rare Ftld Disease Genesmentioning

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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“…In one study, it was seen that, even within a single family where all the affected individuals carried the G66 V variant, many different phenotypes were displayed ranging from CMT2-type axonal neuropathy to spinal muscular atrophy that presented as an ALS-like disease [31]. Another mutation, P80L, is almost exclusively present in patients with ALS [75, 76, 83]. The P80L mutation recently was seen in one control subject, but the authors state that this subject was 57 years of age at the time of the study and may develop symptoms at a later age.…”

Section: Chchd10 and Diseasementioning

confidence: 99%

MNRR1, a Biorganellar Regulator of Mitochondria

Grossman

Purandare

Arshad

et al. 2017

Oxidative Medicine and Cellular Longevity

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The central role of energy metabolism in cellular activities is becoming widely recognized. However, there are many gaps in our knowledge of the mechanisms by which mitochondria evaluate their status and call upon the nucleus to make adjustments. Recently, a protein family consisting of twin CX9C proteins has been shown to play a role in human pathophysiology. We focus here on two family members, the isoforms CHCHD2 (renamed MNRR1) and CHCHD10. The better studied isoform, MNRR1, has the unusual property of functioning in both the mitochondria and the nucleus and of having a different function in each. In the mitochondria, it functions by binding to cytochrome c oxidase (COX), which stimulates respiration. Its binding to COX is promoted by tyrosine-99 phosphorylation, carried out by ABL2 kinase (ARG). In the nucleus, MNRR1 binds to a novel promoter element in COX4I2 and itself, increasing transcription at 4% oxygen. We discuss mutations in both MNRR1 and CHCHD10 found in a number of chronic, mostly neurodegenerative, diseases. Finally, we propose a model of a graded response to hypoxic and oxidative stresses, mediated under different oxygen tensions by CHCHD10, MNRR1, and HIF1, which operate at intermediate and very low oxygen concentrations, respectively.

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Analysis of theCHCHD10gene in patients with frontotemporal dementia and amyotrophic lateral sclerosis from Spain

Cited by 58 publications

References 9 publications

A novel CHCHD10 mutation implicates a Mia40‐dependent mitochondrial import deficit in ALS

A novel CHCHD10 mutation implicates a Mia40‐dependent mitochondrial import deficit in ALS

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

MNRR1, a Biorganellar Regulator of Mitochondria

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