A constant and similar assembly defect of mitochondrial respiratory chain complex I allows rapid identification of NDUFS4 mutations in patients with Leigh syndrome.
Isolated complex I deficiency is a frequent cause of respiratory chain defects in childhood. In this study, we report our systematic approach with blue native PAGE (BN-PAGE) to study mitochondrial respiratory chain assembly in skin fibroblasts from patients with Leigh syndrome and CI deficiency. We describe five new NDUFS4 patients with a similar and constant abnormal BN-PAGE profile and present a meta-analysis of the literature. All NDUFS4 mutations that have been tested with BN-PAGE result in a constant and similar abnormal assembly profile with a complete loss of the fully assembled complex I usually due to a truncated protein and the loss of its canonical cAMP dependent protein kinase phosphorylation consensus site. We also report the association of abnormal brain MRI images with this characteristic BN-PAGE profile as the hallmarks of NDUFS4 mutations and the first founder NDUFS4 mutations in the North-African population.
Université Paris Descartes, Paris, France.
Z
Z
Assouline
M
M
Jambou
M
M
Rio
C
C
Bole-Feysot
P
P
de Lonlay
C
C
Barnerias
I
I
Desguerre
C
C
Bonnemains
C
C
Guillermet
J
J
Steffann
A
A
Munnich
J P
JP
Bonnefont
A
A
Rötig
A S
AS
Lebre
D001921:Brain / Q000473:pathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D042967:Electron Transport Complex I / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007223:Infant; D007888:Leigh Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009245:NADH Dehydrogenase / Q000235:genetics*; D010766:Phosphorylation; D012867:Skin / Q000378:metabolism
D009245:NADH Dehydrogenase; D017868:Cyclic AMP-Dependent Protein Kinases; D042967:Electron Transport Complex I; C427643:NDUFS4 protein, human