CoChat
Sign Up
Cited by 141Mitochondrial Function and PathologyMetabolism and Genetic DisordersGenomics and Rare Diseases

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

Open access
Di Fonzo, Alessio, Ronchi, Dario, Lodi, Tiziana, Fassone, Elisa, Tigano, Marco, Lamperti, Costanza, Corti, Stefania, Bordoni, Andreina +10 more·2009·The American Journal of Human Genetics
DOI 10.1016/j.ajhg.2009.04.004PMC PMC2681006
Open this paper in CoChat — free accountOpen PDF

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.

Integrity signals

Registry

Crossref · 10.1016/j.ajhg.2009.04.004

Cites

33 of 33 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • This rare human GFER mutation causes progressive mitochondrial myopathy and congenital cataracts, hearing loss, and developmental delay in affected individuals.

    “This rare human mutation was found to cause a progressive mitochondrial myopathy and congenital cataracts, hearing loss, and developmental delay in affected individuals.”

    From Redox regulation of mitochondrial function (2012) · cites this paper as [116]

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review