Format

Send to

Choose Destination
Neurogenetics. 2017 Dec;18(4):227-235. doi: 10.1007/s10048-017-0526-4. Epub 2017 Oct 26.

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

Author information

1
Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
2
Department of Medical and Molecular Genetics, King's College London School of Medicine, London, UK.
3
Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, UK.
4
Alder Hey Children's Hospital NHS Foundation Trust, Liverpool, UK.
5
University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
6
Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
7
Department of Neuroradiology, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
8
Institute of Human Genetics, Helmholtz Zentrum München, Oberschleißheim, Germany.
9
Institute of Human Genetics, Technische Universität München, Munich, Germany.
10
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
11
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
12
Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK. robert.taylor@ncl.ac.uk.

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.

KEYWORDS:

Developmental delay; GFM2; Mitochondrial disease; Mitochondrial translation; WES

PMID:
29075935
PMCID:
PMC5705740
DOI:
10.1007/s10048-017-0526-4
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Springer Icon for PubMed Central
Loading ...
Support Center