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 language | English |
|---|---|
| Pages (from-to) | 399-413 |
| Number of pages | 15 |
| Journal | Human Molecular Genetics |
| Volume | 12 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Feb 15 2003 |
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ASJC Scopus subject areas
- Genetics
Cite this
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 journal › Article
}
TY - JOUR
T1 - Constitutive knockout of Surf1 is associated with high embryonic lethality, mitochondrial disease and cytochrome c oxidase deficiency in mice
AU - Agostino, Alessandro
AU - Invernizzi, Federica
AU - Tiveron, Cecilia
AU - Fagiolari, Gigliola
AU - Prelle, Alessandro
AU - Lamantea, Eleonora
AU - Giavazzi, Alessio
AU - Battaglia, Giorgio
AU - Tatangelo, Laura
AU - Tiranti, Valeria
AU - Zeviani, Massimo
PY - 2003/2/15
Y1 - 2003/2/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0037440750&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037440750&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddg038
DO - 10.1093/hmg/ddg038
M3 - Article
C2 - 12566387
AN - SCOPUS:0037440750
VL - 12
SP - 399
EP - 413
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 4
ER -