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Human Molecular Genetics, 2003, Vol. 12, No. 4 399-413
© 2003 Oxford University Press

Constitutive knockout of Surf1 is associated with high embryonic lethality, mitochondrial disease and cytochrome c oxidase deficiency in mice

Alessandro Agostino1, Federica Invernizzi1, Cecilia Tiveron2, Gigliola Fagiolari3, Alessandro Prelle3, Eleonora Lamantea1, Alessio Giavazzi4, Giorgio Battaglia4, Laura Tatangelo2, Valeria Tiranti1 and Massimo Zeviani1,*

1Unit of Molecular Neurogenetics, Pierfranco and Luisa Mariani Center for the Study of Children's Mitochondrial Disorders, Istituto Nazionale Neurologico ‘C. Besta’-IRCCS, Milano, Italy, 2Laboratory of Animal Models, Istituto Regina Elena, Roma, Italy, 3Dino Ferrari Center, Department of Neuroscience, Ospedale Maggiore Policlinico-IRCCS, Milano, Italy and 4Laboratory of Molecular Neuroanatomy, Unit of Experimental Neurophysiology, Istituto Nazionale Neurologico ‘C. Besta’-IRCCS, Milano, Italy

Received October 29, 2002; Revised December 16, 2002; Accepted December 17, 2002

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 ~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.

* To whom correspondence should be addressed at: Unit of Molecular Neurogenetics, National Neurological Institute ‘Carlo Besta’, via Temolo 4, 20126 Milan, Italy. Tel: +39 022394630; Fax: +39 022394619; Email: zeviani{at}tin.it


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