A novel mutation of CHCHD2 p.R8H in a sporadic case of Parkinson's disease

Ikeda, Aya; Mizutani, Takashi; Daida, Kensuke; Nakajima, Sachiko; Conedera, Silvio; Li, Yuanzhe; Yoshino, Hideaki; Oyama, Genko; Funayama, Manabu; Nishioka, Kenya

doi:10.1016/j.parkreldis.2016.10.018

Cited by 15 publications

(6 citation statements)

References 4 publications

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“…No cognitive dysfunction was reported even after 10 years of disease course. Depression was observed without other psychiatric symptoms [99]. A large-scale study in Caucasians did not support the role of CHCHD2 as a PD gene [100].…”

Section: Chchd2 (Park22)mentioning

confidence: 80%

The genetic landscape of Parkinson's disease

2018

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Section: Chchd2 (Park22)mentioning

confidence: 80%

The genetic landscape of Parkinson's disease

2018

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“…However, a large-scale study in PD cases and controls of western European ancestry did not find the T61I mutation (21), suggesting that it is very rare and Asian-specific. Other rare variants in CHCHD2 have been identified in PD patients (5,(21)(22)(23)(24)(25)(26), but their pathogenicity is uncertain due to the lack of segregation data and burden analysis. Thus, although evidence for pathogenicity is strong for Downloaded from https://academic.oup.com/hmg/advance-article-abstract/doi/10.1093/hmg/ddaa028/5739952 by KU Leuven Libraries user on 02 March 2020 HMG-2019-D-00743 10 the T61I mutation, more genetic and functional studies are necessary to determine the pathogenicity of variants in CHCHD2.…”

Section: Discussionmentioning

confidence: 99%

CHCHD2 harboring Parkinson’s disease-linked T61I mutation precipitates inside mitochondria and induces precipitation of wild-type CHCHD2

Cornelissen

Spinazzi

Martin

et al. 2020

Human Molecular Genetics

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The T61I mutation in coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), a protein residing in the mitochondrial intermembrane space (IMS), causes an autosomal dominant form of Parkinson’s disease (PD), but the underlying pathogenic mechanisms are not well understood. Here, we compared the subcellular localization and solubility of wild-type (WT) and T61I mutant CHCHD2 in human cells. We found that mitochondrial targeting of both WT and T61I CHCHD2 depended on the four cysteine residues in the C-terminal coiled-coil-helix-coiled-coil-helix (CHCH) domain but not on the N-terminal predicted mitochondrial targeting sequence. The T61I mutation did not interfere with mitochondrial targeting of the mutant protein but induced its precipitation in the IMS. Moreover, T61I CHCHD2 induced increased mitochondrial production of reactive oxygen species and apoptosis, which was prevented by treatment with anti-oxidants. Retention of T61I CHCHD2 in the cytosol through mutation of the cysteine residues in the CHCH domain prevented its precipitation as well as its apoptosis-inducing effect. Importantly, T61I CHCHD2 potently impaired the solubility of WT CHCHD2. In conclusion, our data show that the T61I mutation renders mutant CHCHD2 insoluble inside mitochondria, suggesting loss of function of the mutant protein. In addition, T61I CHCHD2 exerts a dominant-negative effect on the solubility of WT CHCHD2, explaining the dominant inheritance of this form of PD.

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“…Patients presented variable disease onset (mean age 52 years), good response to levodopa, depression, and the absence of cognitive impairment. A brain autopsy of a CHCHD2 PD patient revealed widespread LB pathology with amyloid plaques and neurofibrillary tangles in the brainstem, limbic regions, and cortex (92)(93)(94). Despite these results, large-scale studies did not support the causative role of CHCHD2 in PD [reviewed in (95)].…”

Section: Ad Genes Awaiting Confirmationmentioning

confidence: 99%

Genotype-Phenotype Correlations in Monogenic Parkinson Disease: A Review on Clinical and Molecular Findings

et al. 2021

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Parkinson disease (PD) is a complex neurodegenerative disorder, usually with multifactorial etiology. It is characterized by prominent movement disorders and non-motor symptoms. Movement disorders commonly include bradykinesia, rigidity, and resting tremor. Non-motor symptoms can include behavior disorders, sleep disturbances, hyposmia, cognitive impairment, and depression. A fraction of PD cases instead is due to Parkinsonian conditions with Mendelian inheritance. The study of the genetic causes of these phenotypes has shed light onto common pathogenetic mechanisms underlying Parkinsonian conditions. Monogenic Parkinsonisms can present autosomal dominant, autosomal recessive, or even X-linked inheritance patterns. Clinical presentations vary from forms indistinguishable from idiopathic PD to severe childhood-onset conditions with other neurological signs. We provided a comprehensive description of each condition, discussing current knowledge on genotype-phenotype correlations. Despite the broad clinical spectrum and the many genes involved, the phenotype appears to be related to the disrupted cell function and inheritance pattern, and several assumptions about genotype-phenotype correlations can be made. The interest in these assumptions is not merely speculative, in the light of novel promising targeted therapies currently under development.

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A novel mutation of CHCHD2 p.R8H in a sporadic case of Parkinson's disease

Cited by 15 publications

References 4 publications

The genetic landscape of Parkinson's disease

The genetic landscape of Parkinson's disease

CHCHD2 harboring Parkinson’s disease-linked T61I mutation precipitates inside mitochondria and induces precipitation of wild-type CHCHD2

Genotype-Phenotype Correlations in Monogenic Parkinson Disease: A Review on Clinical and Molecular Findings

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