Journal Article

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

Alessandro Agostino, Federica Invernizzi, Cecilia Tiveron, Gigliola Fagiolari, Alessandro Prelle, Eleonora Lamantea, Alessio Giavazzi, Giorgio Battaglia, Laura Tatangelo, Valeria Tiranti and Massimo Zeviani

in Human Molecular Genetics

Volume 12, issue 4, pages 399-413
Published in print February 2003 | ISSN: 0964-6906
Published online February 2003 | e-ISSN: 1460-2083 | DOI:
Constitutive knockout of Surf1 is associated with high embryonic lethality, mitochondrial disease and cytochrome c oxidase deficiency in mice

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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.

Journal Article.  9194 words.  Illustrated.

Subjects: Genetics and Genomics

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