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Cited by 141Mitochondrial Function and PathologyMetabolism and Genetic DisordersGenomics and Rare Diseases

The DOI matches its Crossref record; 33 of the 33 references it cites were found in a registry or an index.

The Mitochondrial Disulfide Relay System Protein GFER Is Mutated in Autosomal-Recessive Myopathy with Cataract and Combined Respiratory-Chain Deficiency

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Di Fonzo, Alessio, Ronchi, Dario, Lodi, Tiziana, Fassone, Elisa, Tigano, Marco, Lamperti, Costanza, Corti, Stefania, Bordoni, Andreina, Fortunato, Francesco, Nizzardo, Monica, Napoli, Laura, Donadoni, Chiara, Salani, Sabrina, Saladino, Francesca, Moggio, Maurizio, Bresolin, Nereo, Ferrero, Iliana, Comi, Giacomo P.·2009·The American Journal of Human Genetics
DOI 10.1016/j.ajhg.2009.04.004PMC PMC2681006
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Abstract

A disulfide relay system (DRS) was recently identified in the yeast mitochondrial intermembrane space (IMS) that consists of two essential components: the sulfhydryl oxidase Erv1 and the redox-regulated import receptor Mia40. The DRS drives the import of cysteine-rich proteins into the IMS via an oxidative folding mechanism. Erv1p is reoxidized within this system, transferring its electrons to molecular oxygen through interactions with cytochrome c and cytochrome c oxidase (COX), thereby linking the DRS to the respiratory chain. The role of the human Erv1 ortholog, GFER, in the DRS has been poorly explored. Using homozygosity mapping, we discovered that a mutation in the GFER gene causes an infantile mitochondrial disorder. Three children born to healthy consanguineous parents presented with progressive myopathy and partial combined respiratory-chain deficiency, congenital cataract, sensorineural hearing loss, and developmental delay. The consequences of the mutation at the level of the patient's muscle tissue and fibroblasts were 1) a reduction in complex I, II, and IV activity; 2) a lower cysteine-rich protein content; 3) abnormal ultrastructural morphology of the mitochondria, with enlargement of the IMS space; and 4) accelerated time-dependent accumulation of multiple mtDNA deletions. Moreover, the Saccharomyces cerevisiae erv1(R182H) mutant strain reproduced the complex IV activity defect and exhibited genetic instability of the mtDNA and mitochondrial morphological defects. These findings shed light on the mechanisms of mitochondrial biogenesis, establish the role of GFER in the human DRS, and promote an understanding of the pathogenesis of a new mitochondrial disease.

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Metadata

Authors
Di Fonzo, A., Ronchi, D., Lodi, T., Fassone, E., Tigano, M., Lamperti, C., Corti, S., Bordoni, A., Fortunato, F., Nizzardo, M., Napoli, L., Donadoni, C., Salani, S., Saladino, F., Moggio, M., Bresolin, N., Ferrero, I., & Comi, G. P.
Affiliations
  • University of Milan (IT)
  • University of Parma (IT)
Corresponding author
Comi, Giacomo P.
ORCID
Venue
The American Journal of Human Genetics
Publisher
Elsevier BV
Published
2009-05
Volume
84
Issue
5
Pages
594-604
ISSN
0002-9297 (ISSN-L)
DOI
10.1016/j.ajhg.2009.04.004
PMC
PMC2681006
OpenAlex
W1972934808
Cited by
141
References
33
Citations by year
2026: 3 · 2025: 6 · 2024: 4 · 2022: 7 · 2021: 15 · 2020: 8 · 2019: 4 · 2018: 9 · 2017: 10 · 2016: 7 · 2015: 17 · 2014: 7 · 2013: 12 · 2012: 8
FWCI
4.30
Type
journal article
Language
en
Open access
Licence
Locations
  • The American Journal of Human Genetics (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
mitochondrial intermembrane space, Erv1, oxidative protein folding, autosomal recessive myopathy, congenital cataract, sensorineural hearing loss, developmental delay, mitochondrial DNA deletions, mitochondrial biogenesis, cytochrome c oxidase, consanguinity, homozygosity mapping
MeSH terms
Adolescent, Cataract, Child, Child, Preschool, Consanguinity, Cytochrome Reductases, DNA, Mitochondrial, Humans, Intracellular Membranes, Genetic Linkage, Male, Mutation, Mitochondrial Myopathies, Mitochondrial Proteins, Mitochondrial Diseases, Hearing Loss, Oxidoreductases Acting on Sulfur Group Donors

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