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.
Highlights
Mitochondrial disorders are a genetically and clinically heterogeneous group of diseases which can arise due to defects in the oxidative phosphorylation (OXPHOS) system
Through the application of whole exome sequencing, we have identified previously unpublished recessive GFM2 variants in two unrelated patients with clinical features of mitochondrial disease and biochemical evidence of respiratory chain dysfunction
While Patient 2 shows decreased steady-state levels of mitochondrial-encoded OXPHOS subunits NDUFB8, COXI/COXII and CYTB/CORE2, indicating a combined OXPHOS deficiency, steady-state OXPHOS protein levels were relatively unchanged in Patient 1 when compared to controls (Fig. 3a)
Summary
Mitochondrial disorders are a genetically and clinically heterogeneous group of diseases which can arise due to defects in the oxidative phosphorylation (OXPHOS) system. Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany. Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. All OXPHOS components, with the exception of complex II, are under bi-genomic control and as such are the product of both nuclear DNA and mitochondrial DNA (mtDNA)-encoded proteins [2]. Nuclear genes encode the proteins responsible for mtDNA maintenance, mitochondrial transcription and translation and all other mitochondrial processes. Mutations in either mitochondrial or nuclear genes may compromise ATP synthesis and cause mitochondrial disease. Extensive clinical and genetic heterogeneity makes the identification, characterisation and diagnosis of mitochondrial disease challenging, because clinical features often overlap with other neurological or systemic diseases. The advent of nextgeneration sequencing, whole exome sequencing (WES), has improved the identification of disease-causing pathogenic variants in many different genes resulting in a much greater diagnostic yield than previous candidate gene screening approaches [3]
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