Constitutive knockout of Surf1 is associated with high embryonic lethality, mitochondrial disease and cytochrome c oxidase deficiency in mice.
We report here the creation of a constitutive knockout mouse for SURF1, a gene encoding one of the assembly proteins involved in the formation of cytochrome c oxidase (COX). Loss-of-function mutations of SURF1 cause Leigh syndrome associated with an isolated and generalized COX deficiency in humans. The murine phenotype is characterized by the following hallmarks: (1) high post-implantation embryonic lethality, affecting approximately 90% of the Surf1(-/-) individuals; (2) early-onset mortality of post-natal individuals; (3) highly significant deficit in muscle strength and motor performance; (4) profound and isolated defect of COX activity in skeletal muscle and liver, and, to a lesser extent, heart and brain; (5) morphological abnormalities of skeletal muscle, characterized by reduced histochemical reaction to COX and mitochondrial proliferation; (6) no obvious abnormalities in brain morphology, reflecting the virtual absence of overt neurological symptoms. These results indicate a function for murine Surf1 protein (Surf1p) specifically related to COX and recapitulate, at least in part, the human phenotype. This is the first mammalian model for a nuclear disease gene of a human mitochondrial disorder. Our model constitutes a useful tool to investigate the function of Surf1p, help understand the pathogenesis of Surf1p deficiency in vivo, and evaluate the efficacy of treatment.
Agostino
Alessandro
A
Unit of Molecular Neurogenetics, Pierfranco and Luisa Mariani Center for the Study of Children's Mitochondrial Disorders, Istituto Nazionale Neurologico C. Besta-IRCCS, Milano, Italy.
Invernizzi
Federica
F
Tiveron
Cecilia
C
Fagiolari
Gigliola
G
Prelle
Alessandro
A
Lamantea
Eleonora
E
Giavazzi
Alessio
A
Battaglia
Giorgio
G
Tatangelo
Laura
L
Tiranti
Valeria
V
Zeviani
Massimo
M
D000483:Alleles; D000818:Animals; D015139:Blotting, Southern; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology; D030401:Cytochrome-c Oxidase Deficiency / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000235:genetics*; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008099:Liver / Q000201:enzymology; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D028361:Mitochondrial Diseases / Q000235:genetics*; D024101:Mitochondrial Proteins; D008957:Models, Genetic; D018482:Muscle, Skeletal / Q000201:enzymology; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014018:Tissue Distribution
D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; C092928:Surf-1 protein; D003576:Electron Transport Complex IV