RGD Reference Report - The gene coding for PGC-1alpha modifies age at onset in Huntington's Disease. - Rat Genome Database

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The gene coding for PGC-1alpha modifies age at onset in Huntington's Disease.

Authors: Weydt, P  Soyal, SM  Gellera, C  DiDonato, S  Weidinger, C  Oberkofler, H  Landwehrmeyer, GB  Patsch, W 
Citation: Weydt P, etal., Mol Neurodegener. 2009 Jan 8;4:3. doi: 10.1186/1750-1326-4-3.
RGD ID: 10053656
Pubmed: PMID:19133136   (View Abstract at PubMed)
PMCID: PMC2630305   (View Article at PubMed Central)
DOI: DOI:10.1186/1750-1326-4-3   (Journal Full-text)

Huntington's disease (HD) is one of the most common autosomal dominant inherited, neurodegenerative disorders. It is characterized by progressive motor, emotional and cognitive dysfunction. In addition metabolic abnormalities such as wasting and altered energy expenditure are increasingly recognized as clinical hallmarks of the disease. HD is caused by an unstable CAG repeat expansion in the HD gene (HTT), localized on chromosome 4p16.3. The number of CAG repeats in the HD gene is the main predictor of disease-onset, but the remaining variation is strongly heritable. Transcriptional dysregulation, mitochondrial dysfunction and enhanced oxidative stress have been implicated in the pathogenesis. Recent studies suggest that PGC-1alpha, a transcriptional master regulator of mitochondrial biogenesis and metabolism, is defective in HD. A genome wide search for modifier genes of HD age-of-onset had suggested linkage at chromosomal region 4p16-4p15, near the locus of PPARGC1A, the gene coding for PGC-1alpha. We now present data of 2-loci PPARGC1A block 2 haplotypes, showing an effect upon age-at-onset in 447 unrelated HD patients after statistical consideration of CAG repeat lengths in both HTT alleles. Block 1 haplotypes were not associated with the age-at-onset. Homozygosity for the 'protective' block 2 haplotype was associated with a significant delay in disease onset. To our knowledge this is the first study to show clinically relevant effects of the PGC-1alpha system on the course of Huntington's disease in humans.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Huntington's disease no_associationIAGP 10053656DNA:missense mutation:cds:pT612M (rs3736265) (human)RGD 
Huntington's disease onsetIAGP 10053656DNA:snps and haplotypes:multiple (human)RGD 
Huntington's disease no_associationISOPPARGC1A (Homo sapiens)10053656; 10053656DNA:missense mutation:cds:pT612M (rs3736265) (human)RGD 
Huntington's disease onsetISOPPARGC1A (Homo sapiens)10053656; 10053656DNA:snps and haplotypes:multiple (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ppargc1a  (PPARG coactivator 1 alpha)

Genes (Mus musculus)
Ppargc1a  (peroxisome proliferative activated receptor, gamma, coactivator 1 alpha)

Genes (Homo sapiens)
PPARGC1A  (PPARG coactivator 1 alpha)


Additional Information