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

被引:13
作者
Glasgow, Ruth I. C. [1 ]
Thompson, Kyle [1 ]
Barbosa, Ines A. [2 ]
He, Langping [1 ]
Alston, Charlotte L. [1 ]
Deshpande, Charu [2 ]
Simpson, Michael A. [2 ]
Morris, Andrew A. M. [3 ,4 ]
Neu, Axel [5 ]
Loebel, Ulrike [6 ]
Hall, Julie [7 ]
Prokisch, Holger [8 ,9 ]
Haack, Tobias B. [9 ,10 ]
Hempel, Maja [11 ]
McFarland, Robert [1 ]
Taylor, Robert W. [1 ]
机构
[1] Newcastle Univ, Sch Med, Inst Neurosci, Wellcome Ctr Mitochondrial Res, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England
[2] Kings Coll London, Dept Med & Mol Genet, Sch Med, London, England
[3] Univ Manchester, Sch Biol Sci, Div Evolut & Genom Sci, Manchester, Lancs, England
[4] Alder Hey Childrens Hosp NHS Fdn Trust, Liverpool, Merseyside, England
[5] Univ Med Ctr Hamburg Eppendorf, Univ Childrens Hosp, Hamburg, Germany
[6] Univ Med Ctr Hamburg Eppendorf, Dept Diagnost & Intervent Neuroradiol, Hamburg, Germany
[7] Royal Victoria Infirm, Dept Neuroradiol, Newcastle Upon Tyne, Tyne & Wear, England
[8] Helmholtz Zentrum Munchen, Inst Human Genet, Oberschleissheim, Germany
[9] Tech Univ Munich, Inst Human Genet, Munich, Germany
[10] Univ Tubingen, Inst Med Genet & Appl Genom, Tubingen, Germany
[11] Univ Med Ctr Hamburg Eppendorf, Inst Human Genet, Hamburg, Germany
基金
英国医学研究理事会; 欧盟地平线“2020”;
关键词
WES; GFM2; Mitochondrial translation; Developmental delay; Mitochondrial disease; TRANSFER-RNA-SYNTHETASES; MUTATIONS; SEQUENCE; GENOME;
D O I
10.1007/s10048-017-0526-4
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
引用
收藏
页码:227 / 235
页数:9
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