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Open Access 01-12-2017 | Original Article

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

Authors: Ruth I. C. Glasgow, Kyle Thompson, Inês A. Barbosa, Langping He, Charlotte L. Alston, Charu Deshpande, Michael A. Simpson, Andrew A. M. Morris, Axel Neu, Ulrike Löbel, Julie Hall, Holger Prokisch, Tobias B. Haack, Maja Hempel, Robert McFarland, Robert W. Taylor

Published in: Neurogenetics | Issue 4/2017

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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Title: Novel GFM2 variants associated with early-onset neurological presentations of mitochondrial disease and impaired expression of OXPHOS subunits
Authors: Ruth I. C. Glasgow
Kyle Thompson
Inês A. Barbosa
Langping He
Charlotte L. Alston
Charu Deshpande
Michael A. Simpson
Andrew A. M. Morris
Axel Neu
Ulrike Löbel
Julie Hall
Holger Prokisch
Tobias B. Haack
Maja Hempel
Robert McFarland
Robert W. Taylor
Publication date: 01-12-2017
Publisher: Springer Berlin Heidelberg
Published in: Neurogenetics / Issue 4/2017
Print ISSN: 1364-6745
Electronic ISSN: 1364-6753
DOI: https://doi.org/10.1007/s10048-017-0526-4

At a glance: The STEP trials

Springer Medicine

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

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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