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

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

Research output: Contribution to journalArticle

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Abstract

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 Surfl-1- 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.

Original languageEnglish
Pages (from-to)399-413
Number of pages15
JournalHuman Molecular Genetics
Volume12
Issue number4
DOIs
Publication statusPublished - Feb 15 2003

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Cytochrome-c Oxidase Deficiency
Mitochondrial Diseases
Oxidoreductases
Skeletal Muscle
Leigh Disease
Phenotype
Protein Deficiency
Proteins
Brain
Muscle Strength
Electron Transport Complex IV
Knockout Mice
Genes
Mutation
Mortality
Liver

ASJC Scopus subject areas

  • Genetics

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Constitutive knockout of Surf1 is associated with high embryonic lethality, mitochondrial disease and cytochrome c oxidase deficiency in mice. / Agostino, Alessandro; Invernizzi, Federica; Tiveron, Cecilia; Fagiolari, Gigliola; Prelle, Alessandro; Lamantea, Eleonora; Giavazzi, Alessio; Battaglia, Giorgio; Tatangelo, Laura; Tiranti, Valeria; Zeviani, Massimo.

In: Human Molecular Genetics, Vol. 12, No. 4, 15.02.2003, p. 399-413.

Research output: Contribution to journalArticle

Agostino, Alessandro ; Invernizzi, Federica ; Tiveron, Cecilia ; Fagiolari, Gigliola ; Prelle, Alessandro ; Lamantea, Eleonora ; Giavazzi, Alessio ; Battaglia, Giorgio ; Tatangelo, Laura ; Tiranti, Valeria ; Zeviani, Massimo. / Constitutive knockout of Surf1 is associated with high embryonic lethality, mitochondrial disease and cytochrome c oxidase deficiency in mice. In: Human Molecular Genetics. 2003 ; Vol. 12, No. 4. pp. 399-413.
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