期刊
NEUROGENETICS
卷 18, 期 4, 页码 227-235出版社
SPRINGER
DOI: 10.1007/s10048-017-0526-4
关键词
WES; GFM2; Mitochondrial translation; Developmental delay; Mitochondrial disease
资金
- 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]
- Lily Foundation
- UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children
- Department of Health via the NIHR comprehensive Biomedical Research Centre
- King's College London
- NIHR/CSO Healthcare Science Research Fellowship from the National Institute for Health Research [NIHR-HCS-D12-03-04]
- German Federal Ministry of Education and Research (BMBF) [FKZ 01ZX1405C]
- German Bundesministerium fur Bildung und Forschung (BMBF)
- Horizon 2020 through E-Rare project GENOMIT [01GM1603, 01GM1207]
- EU [633974]
- National Institute for Health Research [NIHR-HCS-D12-03-04] Funding Source: researchfish
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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