RGD Reference Report - Ndufc2 Gene Inhibition Is Associated With Mitochondrial Dysfunction and Increased Stroke Susceptibility in an Animal Model of Complex Human Disease. - Rat Genome Database

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Ndufc2 Gene Inhibition Is Associated With Mitochondrial Dysfunction and Increased Stroke Susceptibility in an Animal Model of Complex Human Disease.

Authors: Rubattu, S  Di Castro, S  Schulz, H  Geurts, AM  Cotugno, M  Bianchi, F  Maatz, H  Hummel, O  Falak, S  Stanzione, R  Marchitti, S  Scarpino, S  Giusti, B  Kura, A  Gensini, GF  Peyvandi, F  Mannucci, PM  Rasura, M  Sciarretta, S  Dwinell, MR  Hubner, N  Volpe, M 
Citation: Rubattu S, etal., J Am Heart Assoc. 2016 Feb 17;5(2). pii: e002701. doi: 10.1161/JAHA.115.002701.
RGD ID: 11040458
Pubmed: PMID:26888427   (View Abstract at PubMed)
PMCID: PMC4802485   (View Article at PubMed Central)
DOI: DOI:10.1161/JAHA.115.002701   (Journal Full-text)

BACKGROUND: The genetic basis of stroke susceptibility remains to be elucidated. STR1 quantitative trait locus (STR1/QTL) was identified on rat chromosome 1 of stroke-prone spontaneously hypertensive rat (SHRSP) upon Japanese-style stroke-permissive diet (JD), and it contributes to 20% of the stroke phenotype variance. METHODS AND RESULTS: Nine hundred eighty-six probe sets mapping on STR1 were selected from the Rat RAE230A array and screened through a microarray differential expression analysis in brains of SHRSP and stroke-resistant SHR (SHRSR) fed with either regular diet or JD. The gene encoding Ndufc2 (NADH dehydrogenase [ubiquinone] 1 subunit), mapping 8 Mb apart from STR1/QTL Lod score peak, was found significantly down-regulated under JD in SHRSP compared to SHRSR. Ndufc2 disruption altered complex I assembly and activity, reduced mitochondrial membrane potential and ATP levels, and increased reactive oxygen species production and inflammation both in vitro and in vivo. SHRSR carrying heterozygous Ndufc2 deletion showed renal abnormalities and stroke occurrence under JD, similarly to SHRSP. In humans, T allele variant at NDUFC2/rs11237379 was associated with significant reduction in gene expression and with increased occurrence of early-onset ischemic stroke by recessive mode of transmission (odds ratio [OR], 1.39; CI, 1.07-1.80; P=0.012). Subjects carrying TT/rs11237379 and A allele variant at NDUFC2/rs641836 had further increased risk of stroke (OR=1.56; CI, 1.14-2.13; P=0.006). CONCLUSIONS: A significant reduction of Ndufc2 expression causes complex I dysfunction and contributes to stroke susceptibility in SHRSP. Moreover, our current evidence may suggest that Ndufc2 can contribute to an increased occurrence of early-onset ischemic stroke in humans.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Stroke susceptibilityIAGP 11040458DNA:SNPs more ...RGD 
Stroke  ISONdufc2 (Rattus norvegicus)11040458; 11040458incidence 40% in heterozygous SHR-Ndufc2 rats vs 0% in parental SHR rats after 3 months of stroke-permissive dietRGD 
Stroke susceptibilityISONDUFC2 (Homo sapiens)11040458; 11040458DNA:SNPs more ...RGD 
Stroke  IMP 11040458incidence 40% in heterozygous SHR-Ndufc2 rats vs 0% in parental SHR rats after 3 months of stroke-permissive dietRGD 
Stroke  IMP 11040458DNA:deletion:exon 1:heterozygous 107 bp deletionRGD 
Stroke inducedIMPcontrolled sodium content diet and controlled potassium content diet and controlled protein content diet11040458 RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
decreased body weight  IAGP 11040458compared to SHR/BbbRGD 
decreased susceptibility to ischemic brain injury inducedIMPcontrolled sodium content diet and controlled potassium content diet and controlled protein content diet11040458compared to SHRSP/BbbRGD 
failure of embryo implantation  IMP 11040458DNA:deletion:exon1:no homozygous knockout embryos found at implantation stageRGD 
failure of embryo implantation  IMP 11040458; 11040458DNA:deletion:exon 1:no homozygous knockout embryos found at implantation stageRGD 
failure of embryo implantation  IMP 11040458; 11040458no homozygous knockout embryos found at implantation stageRGD 
increased susceptibility to ischemic brain injury inducedIMPcontrolled sodium content diet and controlled potassium content diet and controlled protein content diet11040458compared to SHR/BbbRGD 
increased urine protein level  IMP 11040458DNA:deletion:exon1:heterozygous 107 bp deletionRGD 
increased urine protein level  IMP 11040458 RGD 
increased urine protein level inducedIMPcontrolled sodium content diet and controlled potassium content diet and controlled protein content diet11040458compared to SHR/BbbRGD 
increased urine protein level inducedIAGPcontrolled sodium content diet and controlled potassium content diet and controlled protein content diet11040458compared to SHR/BbbRGD 

Objects Annotated

Genes (Rattus norvegicus)
Ndufc2  (NADH:ubiquinone oxidoreductase subunit C2)
Ndufc2em1Mcwi  (NADH dehydrogenase (ubiquinone) 1, subcomplex unknown, 2; zinc finger nuclease induced mutant 1, Medical College of Wisconsin)
Ndufc2em2Mcwi  (NADH dehydrogenase (ubiquinone) 1, subcomplex unknown, 2; zinc finger nuclease induced mutant 2, Medical College of Wisconsin)

Genes (Mus musculus)
Ndufc2  (NADH:ubiquinone oxidoreductase subunit C2)

Genes (Homo sapiens)
NDUFC2  (NADH:ubiquinone oxidoreductase subunit C2)

Strains
SHR-Ndufc2em1Mcwi  (NA)
SHR-Ndufc2em2Mcwi-/+  (SHR-Ndufc2em2Mcwi-/Ndufc2em2Mcwi+)
SHR-Ndufc2em2Mcwi  (NA)
SHRSP/Bbb  (NA)


Additional Information