Whole exome sequencing reveals a homozygous C1QBP deletion as the cause of progressive external ophthalmoplegia and multiple mtDNA deletions

Guo, Le; Govindaraj, Periyasamy; Kievit, M. T.; Coo, I.F.M. de; Gerards, Mike; Hellebrekers, Debby M.E.I.; Stassen, Alphons P. M.; Gayathri, Narayanappa; Taly, Arun B.; Sankaran, Bindu Parayil; Smeets, Hubert J.M.

doi:10.1016/j.nmd.2021.06.014

Neuromuscular Disorders

2021

DOI: 10.1016/j.nmd.2021.06.014

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Whole exome sequencing reveals a homozygous C1QBP deletion as the cause of progressive external ophthalmoplegia and multiple mtDNA deletions

Le Guo

Periyasamy Govindaraj

M. T. Kievit

et al.

Abstract: Whole exome sequencing reveals a homozygous C1QBP deletion as the cause of progressive external ophthalmoplegia and multiple mtDNA deletions, Neuromuscular Disorders (2021), doi:

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CHCHD10 mutations induce tissue-specific mitochondrial DNA deletions with a distinct signature

Shammas,

Nie,

Gilsrud

et al. 2023

Human Molecular Genetics

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Mutations affecting the mitochondrial intermembrane space protein CHCHD10 cause human disease, but it is not known why different amino acid substitutions cause markedly different clinical phenotypes, including amyotrophic lateral sclerosis-frontotemporal dementia, spinal muscular atrophy Jokela-type, isolated autosomal dominant mitochondrial myopathy and cardiomyopathy. CHCHD10 mutations have been associated with deletions of mitochondrial DNA (mtDNA deletions), raising the possibility that these explain the clinical variability. Here, we sequenced mtDNA obtained from hearts, skeletal muscle, livers and spinal cords of WT and Chchd10 G58R or S59L knockin mice to characterise the mtDNA deletion signatures of the two mutant lines. We found that the deletion levels were higher in G58R and S59L mice than in WT mice in some tissues depending on the Chchd10 genotype, and the deletion burden increased with age. Furthermore, we observed that the spinal cord was less prone to the development of mtDNA deletions than the other tissues examined. Finally, in addition to accelerating the rate of naturally occurring deletions, Chchd10 mutations also led to the accumulation of a novel set of deletions characterised by shorter direct repeats flanking the deletion breakpoints. Our results indicate that Chchd10 mutations in mice induce tissue-specific deletions which may also contribute to the clinical phenotype associated with these mutations in humans.

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CHCHD10 mutations induce tissue-specific mitochondrial DNA deletions with a distinct signature

Shammas,

Nie,

Gilsrud

et al. 2023

Human Molecular Genetics

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Atheromatosis of the Scalp: A Novel Feature of Chronic Progressive External Ophthalmoplegia Plus Due to a Single Mitochondrial DNA Deletion

Finsterer¹

2021

Cureus

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Chronic progressive external ophthalmoplegia (CPEO) manifests phenotypically as ptosis with ophthalmoplegia or CPEO-plus, with the affection of muscles or organs other than the extra-ocular eye muscles. Herein, a case of CPEO-plus caused by a single mitochondrial DNA (mtDNA) deletion is represented, along with several previously unreported phenotypic features. The patient is a 76-year-old Caucasian female who had experienced slowly progressive bilateral ptosis since the age of 15, followed by gradual ophthalmoparesis without double vision. Since the age of 56, she had developed mild quadriparesis, depression, easy fatigability, hypersomnia, a facial tic, optic atrophy, cataract, glaucoma, hepatomegaly, hepatic steatosis, cholecystolithiasis, diverticulosis, hyperhidrosis, mild hyper-creatine-kinase-emia, hyperlipidemia, and hyperuricemia. Moreover, she had faced previously unreported manifestations of mitochondrial disorders, psoriasis, and multiple scalp atheromas. The phenotype and a single 5kb mtDNA deletion were employed to diagnose CPEO-plus. This case demonstrates that the phenotypic spectrum of CPEO-plus is broader than expected, that psoriasis and scalp atheromas are unique features of a mitochondrial disorder, and that CPEO progresses to CPEO-plus during the years.

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Whole exome sequencing reveals a homozygous C1QBP deletion as the cause of progressive external ophthalmoplegia and multiple mtDNA deletions

Abstract: Whole exome sequencing reveals a homozygous C1QBP deletion as the cause of progressive external ophthalmoplegia and multiple mtDNA deletions, Neuromuscular Disorders (2021), doi:

Cited by 2 publications

References 23 publications

CHCHD10 mutations induce tissue-specific mitochondrial DNA deletions with a distinct signature

CHCHD10 mutations induce tissue-specific mitochondrial DNA deletions with a distinct signature

Atheromatosis of the Scalp: A Novel Feature of Chronic Progressive External Ophthalmoplegia Plus Due to a Single Mitochondrial DNA Deletion

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