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

Lookup NU author(s): Ruth Glasgow, Dr Kyle Thompson, Dr Langping He, Dr Charlotte Alston, Professor Bobby McFarlandORCiD, Professor Robert Taylor



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.

Publication metadata

Author(s): Glasgow RIC, Thompson K, Barbosa IA, He L, Alston CL, Deshpande C, Simpson MA, Morris AAM, Neu A, Löbel U, Hall J, Prokisch H, Haack TB, Hempel M, McFarland R, Taylor RW

Publication type: Article

Publication status: Published

Journal: Neurogenetics

Year: 2017

Volume: 18

Issue: 4

Pages: 227-235

Print publication date: 01/12/2017

Online publication date: 26/10/2017

Acceptance date: 03/10/2017

Date deposited: 02/11/2017

ISSN (print): 1364-6745

ISSN (electronic): 1364-6753

Publisher: Springer


DOI: 10.1007/s10048-017-0526-4

PubMed id: 29075935


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Funder referenceFunder name
203105/Z/16/ZWellcome Trust