title: The variability of the harlequin mouse phenotype resembles that of human mitochondrial-complex I-deficiency syndromes.
abstract: BACKGROUND
  Despite the considerable progress made in understanding the molecular bases of mitochondrial diseases, no effective treatments have been developed to date. Faithful animal models would be extremely helpful for designing such treatments. We showed previously that the Harlequin mouse phenotype was due to a specific mitochondrial complex I deficiency resulting from the loss of the Apoptosis Inducing Factor (Aif) protein.
  
  
  RESULTS
  Here, we conducted a detailed evaluation of the Harlequin mouse phenotype, including the biochemical abnormalities in various tissues. We observed highly variable disease expression considering both severity and time course progression. In each tissue, abnormalities correlated with the residual amount of the respiratory chain complex I 20 kDa subunit, rather than with residual Aif protein. Antioxidant enzyme activities were normal except in skeletal muscle, where they were moderately elevated.
  
  
  CONCLUSIONS
  Thus, the Harlequin mouse phenotype appears to result from mitochondrial respiratory chain complex I deficiency. Its features resemble those of human complex I deficiency syndromes. The Harlequin mouse holds promise as a model for developing treatments for complex I deficiency syndromes.
authors.affiliation: Inserm, U676, Hôpital Robert Debré, Paris, France.
authors.forename: Paule
authors.initials: P
authors.lastname: Bénit
authors.forename: Sergio
authors.initials: S
authors.lastname: Goncalves
authors.forename: Emmanuel Philippe
authors.initials: EP
authors.lastname: Dassa
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Brière
authors.forename: Pierre
authors.initials: P
authors.lastname: Rustin
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D042967:Electron Transport Complex I / Q000172:deficiency* / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008928:Mitochondria; D008957:Models, Genetic; D010641:Phenotype; D015203:Reproducibility of Results; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors
chemical_list: D000975:Antioxidants; D013482:Superoxide Dismutase; D042967:Electron Transport Complex I
references.citation: J Biol Chem. 2006 Jul 7;281(27):18507-18
references.pmid: 16644725
references.citation: Am J Physiol Cell Physiol. 2005 Jun;288(6):C1440-50
references.pmid: 15647387
references.citation: EMBO J. 2004 Nov 24;23(23):4679-89
references.pmid: 15526035
references.citation: Cell Metab. 2008 Apr;7(4):312-20
references.pmid: 18396137
references.citation: Cell Death Differ. 2006 Feb;13(2):354-7
references.pmid: 16195738
references.citation: Am J Med Genet. 2001 Spring;106(1):4-17
references.pmid: 11579420
references.citation: J Biol Chem. 2004 Jul 23;279(30):31761-8
references.pmid: 15166242
references.citation: Nature. 2001 Mar 29;410(6828):549-54
references.pmid: 11279485
references.citation: Clin Chim Acta. 2006 Dec;374(1-2):81-6
references.pmid: 16828729
references.citation: Am J Med Genet A. 2006 Oct 15;140(20):2207-11
references.pmid: 16969871
references.citation: Nat Genet. 1999 Jan;21(1):133-7
references.pmid: 9916807
references.citation: Mol Cell Biol. 2005 Dec;25(23):10261-72
references.pmid: 16287843
references.citation: Muscle Nerve. 2006 Sep;34(3):265-83
references.pmid: 16810684
references.citation: Eur J Biochem. 1974 Sep 16;47(3):469-74
references.pmid: 4215654
references.citation: Cell. 2007 Nov 2;131(3):476-91
references.pmid: 17981116
references.citation: Mol Cell Biochem. 2008 Jul;314(1-2):45-50
references.pmid: 18414996
references.citation: J Pediatr. 2003 Aug;143(2):208-12
references.pmid: 12970634
references.citation: Ann Neurol. 2007 Jan;61(1):73-83
references.pmid: 17262856
references.citation: Trends Mol Med. 2001 Dec;7(12):578-81
references.pmid: 11733222
references.citation: Bioessays. 2006 Aug;28(8):834-43
references.pmid: 16927311
references.citation: Cell Biochem Funct. 2008 Sep-Oct;26(5):598-602
references.pmid: 18508388
references.citation: Curr Opin Neurol. 2007 Oct;20(5):564-71
references.pmid: 17885446
references.citation: Anal Biochem. 1976 May 7;72:248-54
references.pmid: 942051
references.citation: Nature. 2002 Sep 26;419(6905):367-74
references.pmid: 12353028
references.citation: Circ Res. 2005 Jun 24;96(12):e92-e101
references.pmid: 15933268
references.citation: Cell Death Differ. 2008 Jun;15(6):1009-18
references.pmid: 18309327
references.citation: Proc Natl Acad Sci U S A. 1999 Feb 2;96(3):846-51
references.pmid: 9927656
references.citation: EMBO J. 2000 Apr 17;19(8):1777-83
references.pmid: 10775262
references.citation: J Am Coll Cardiol. 2006 Aug 15;48(4):824-32
references.pmid: 16904556
references.citation: Nat Genet. 2001 Feb;27(2):181-6
references.pmid: 11175786
references.citation: Biochim Biophys Acta. 2004 Dec 6;1659(2-3):172-7
references.pmid: 15576049
references.citation: Pediatrics. 1999 Feb;103(2):428-33
references.pmid: 9925836
references.citation: EMBO J. 2006 Sep 6;25(17):4061-73
references.pmid: 16917506
references.citation: Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):9918-23
references.pmid: 16788063