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Cited by 17Mitochondrial Function and PathologyMetabolism and Genetic DisordersGenomics and Rare Diseases

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Novel GFM2 variants associated with early-onset neurological presentations of mitochondrial disease and impaired expression of OXPHOS subunits

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Glasgow, Ruth I. C., Thompson, Kyle, Barbosa, Inês A., He, Langping, Alston, Charlotte L., Deshpande, Charu, Simpson, Michael A., Morris, Andrew A. M., Neu, Axel, Löbel, Ulrike, Hall, Julie, Prokisch, Holger, Haack, Tobias B., Hempel, Maja, McFarland, Robert, Taylor, Robert W.·2017·neurogenetics
DOI 10.1007/s10048-017-0526-4PMC PMC5705740
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Abstract

Mitochondrial diseases are characterised by clinical, molecular and functional heterogeneity, reflecting their bi-genomic control. The nuclear gene GFM2 encodes mtEFG2, a protein with an essential role during the termination stage of mitochondrial translation. We present here two unrelated patients harbouring different and previously unreported compound heterozygous (c.569G>A, p.(Arg190Gln); c.636delA, p.(Glu213Argfs*3)) and homozygous (c.275A>C, p.(Tyr92Ser)) recessive variants in GFM2 identified by whole exome sequencing (WES) together with histochemical and biochemical findings to support the diagnoses of pathological GFM2 variants in each case. Both patients presented similarly in early childhood with global developmental delay, raised CSF lactate and abnormalities on cranial MRI. Sanger sequencing of familial samples confirmed the segregation of bi-allelic GFM2 variants with disease, while investigations into steady-state mitochondrial protein levels revealed respiratory chain subunit defects and loss of mtEFG2 protein in muscle. These data demonstrate the effects of defective mtEFG2 function, caused by previously unreported variants, confirming pathogenicity and expanding the clinical phenotypes associated with GFM2 variants.

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  • Combined oxidative phosphorylation deficiency 39 and combined oxidative phosphorylation defect type 26 are associated with neurological presentations of mitochondrial disease, including hypotonia, seizures, and features of Leigh syndrome.

    “Combined oxidative phosphorylation deficiency 39 and combined oxidative phosphorylation defect type 26 are associated with neurological presentations of mitochondrial disease, including hypotonia, seizures, and features of Leigh syndrome66.”

    From Few shot learning for phenotype-driven diagnosis of patients with rare genetic diseases (2025) · cites this paper as [66]

    The Patient 2 section reports seizures and severe axial hypotonia in a patient with GFM2 variants, and the Discussion reports Leigh syndrome in an earlier GFM2 family. The Introduction mentions neurological disease associated with GFM1 mutations, but our copy does not establish the same set of symptoms for both numbered deficiency types or identify them by those names. Page numbers are unavailable in our copy. (LLM, conf=0.85)

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Research works printed but not linked: 27

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Metadata

Authors
Glasgow, R. I. C., Thompson, K., Barbosa, I. A., He, L., Alston, C. L., Deshpande, C., Simpson, M. A., Morris, A. A. M., Neu, A., Löbel, U., Hall, J., Prokisch, H., Haack, T. B., Hempel, M., McFarland, R., & Taylor, R. W.
Affiliations
  • Wellcome Centre for Mitochondrial Research (GB)
  • King's College London (GB)
  • University of Manchester (GB)
  • University Medical Center Hamburg-Eppendorf (DE)
  • Royal Victoria Infirmary (GB)
  • Helmholtz Munich (DE)
  • Institut für Humangenetik (DE)
Corresponding author
Taylor, Robert W.
ORCID
Venue
neurogenetics
Publisher
Springer Science and Business Media LLC
Published
2017-10-26
Volume
18
Issue
4
Pages
227-235
ISSN
  • 1364-6745 (ISSN-L)
  • 1364-6753
DOI
10.1007/s10048-017-0526-4
PMC
PMC5705740
OpenAlex
W2766259519
Cited by
17
References
1
Citations by year
2026: 2 · 2025: 2 · 2024: 6 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 3 · 2019: 1
FWCI
0.45
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurogenetics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Portal (King's College London) (publishedVersion, cc-by)
  • mediaTUM (Technical University of Munich) (submittedVersion)
  • Site cant be reached (submittedVersion)
  • PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
Funders
  • The Lily Foundation
  • Wellcome Centre for Mitochondrial Research (203105/Z/16/Z)
  • Medical Research Council (MRC) Centre for Translational Research in Neuromuscular Disease
  • Mitochondrial Disease Patient Cohort (UK) (G0800674)
  • UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children
  • NIHR/CSO Healthcare Science Research Fellowship (NIHR-HCS-D12-03-04)
  • German Federal Ministry of Education and Research (BMBF) (FKZ 01ZX1405C)
  • German Bundesministerium für Bildung und Forschung (BMBF) and Horizon2020 (01GM1603, 01GM1207)
  • EU Horizon2020 Collaborative Research Project SOUND (633974)
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 disease, compound heterozygosity, novel variants, global developmental delay, CSF lactate, pathogenicity
MeSH terms
Child, Female, Homozygote, Humans, Male, Mitochondria, Mutation, Pedigree, Phenotype, Peptide Elongation Factor G, Mitochondrial Proteins, Mitochondrial Diseases, Exome

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