PGC-1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington disease.

BACKGROUND: Huntington disease (HD) is an inherited neurodegenerative disease caused by an abnormal expansion of a CAG repeat in the huntingtin HTT (HD) gene. The primary genetic determinant of the age at onset (AO) is the length of the HTT CAG repeat; however, the remaining genetic contribution to the AO of HD has largely not been elucidated. Recent studies showed that impaired functioning of the peroxisome proliferator-activated receptor gamma coactivator 1a (PGC-1alpha) contributes to mitochondrial dysfunction and appears to play an important role in HD pathogenesis. Further genetic evidence for involvement of PGC-1alpha in HD pathogenesis was generated by the findings that sequence variations in the PPARGC1A gene encoding PGC-1alpha exert modifying effects on the AO in HD. In this study, we hypothesised that polymorphisms in PGC-1alpha downstream targets might also contribute to the variation in the AO. RESULTS: In over 400 German HD patients, polymorphisms in the nuclear respiratory factor 1 gene, NRF-1, and the mitochondrial transcription factor A, encoded by TFAM showed nominally significant association with AO of HD. When combining these results with the previously described modifiers rs7665116 in PPARGC1A and C7028T in the cytochrome c oxidase subunit I (CO1, mt haplogroup H) in a multivariable model, a substantial proportion of the variation in AO can be explained by the joint effect of significant modifiers and their interactions, respectively. CONCLUSIONS: These results underscore that impairment of mitochondrial function plays a critical role in the pathogenesis of HD and that upstream transcriptional activators of PGC-1alpha may be useful targets in the treatment of HD.

Age at onset in Huntington's disease: replication study on the associations of ADORA2A, HAP1 and OGG1.

In previous candidate gene studies, associations of the age at onset (AO) in Huntington disease (HD) have been reported with genetic variations in the genes encoding adenosinergic A(2A) receptor (ADORA2A), human huntingtin-associated protein-1 (HAP1) and the single base excision repair enzyme, 7,8-dihydro-8-oxoguanine-DNA glycosylase (OGG1). Here, we sought to replicate these associations in an established study population of 419 unrelated German HD patients. AO was defined as the age at which the first motor signs of HD appeared, motor AO (mAO). For 215 patients, also information about the first behavioural or cognitive signs of HD was available, so that we also tested for an association with the earliest AO. No association was found with OGG1. For HAP1, we found modest evidence for association with the same risk allele as in the original sample and mAO. Yet, we replicated the previously reported association between the original ADORA2A polymorphism when using the earliest AO. Additionally, we identified new associations in the same gene, thus further supporting the potential contribution of ADORA2A to the pathogenesis of HD.

Mitochondrial haplogroup H correlates with ATP levels and age at onset in Huntington disease.

Mitochondrial dysfunction has been implicated in the pathogenesis of Huntington disease (HD), a primarily neurodegenerative disorder that results from an expansion in the polymorphic trinucleotide CAG tract in the HD gene. In order to evaluate whether mitochondrial DNA (mtDNA) variation contributes to HD phenotype we genotyped 13 single nucleotide polymorphisms (SNPs) that define the major European mtDNA haplogroups in 404 HD patients. Genotype-dependent functional effects on intracellular ATP concentrations were assessed in peripheral leukocytes. In patients carrying the most common haplogroup H (48.3%), we demonstrate a significantly lower age at onset (AO). In combination with PGC-1 alpha genotypes, 3.8% additional residual variance in HD AO can be explained. Intracellular ATP concentrations in HD patients carrying the cytochrome c oxidase subunit I (CO1) 7028C allele defining haplogroup H were significantly higher in comparison to non-H individuals (mean +/- SEM, 599 +/- 51.8 ng/ml, n = 14 vs. 457.5 +/- 40.4 ng/ml, p = 0.03, n = 9). In contrast, ATP concentrations in cells of HD patients independent from mtDNA haplogroup showed no significant differences in comparison to matched healthy controls. Our data suggest that an evolutionarily advantageous mitochondrial haplogroup is associated with functional mitochondrial alterations and may modify disease phenotype in the context of neurodegenerative conditions such as HD.

Novel cause of hereditary obstructive azoospermia: a T2 allele in the CFTR gene.

Congenital bilateral absence of the vas deferens (CBAVD) is a frequent cause of obstructive azoospermia, and caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. A novel TG(13)T(2) allele was identified in a CBAVD patient with no clinical cystic fibrosis phenotype, normal pancreatic function, normal sweat chloride concentrations and no Y chromosome microdeletions. This case was studied for CFTR mutations, IVS8-poly(T), and M470V exon 10 missense polymorphism. One novel allele was detected in the (TG)(m)(T)(n) loci that had not been reported previously. This patient carried a [TG(11)T(9); R117H; p.Met470Val] haplotype on the other chromosome. Since the TG(13)T(2) allele was a compound heterozygote with R117H mutation, it was difficult to judge the severity of this allele. To better understand the complex regulation of exon 9 splicing, the levels of correctly spliced CFTR transcripts in CFTR-expressing epithelial cells derived from vas deferens and epididymis were analysed. These data emphasize the role of the T2 allele in CBAVD, and identify the T2 allele as a severe CBAVD disease-causing mutation. According to the data, the longer (TG)(m) polymorphic tract increases the proportion of transcripts with exon 9 deletion (9-), but only when activated by the short T allele.

PGC-1alpha as modifier of onset age in Huntington disease.

Although there is a strong correlation between CAG repeat length and age at onset (AO) of motor symptoms, individual Huntington disease (HD) patients may differ dramatically in onset age and disease manifestations despite similar CAG repeat lengths. This has led to a search for genetic factors that influence AO. In order to identify such a genetic modifier, we analysed polymorphisms in the PGC-1alpha gene. Recent data indicate inhibition of PGC-1alpha function by mutant Htt supporting a link between transcriptional deregulation and mitochondrial dysfunction in HD. In > 400 HD patients, a polymorphism located within intron 2, a potential recombination hot spot, explains a small, but statistically significant, amount of the variability in AO. Our data suggest that PGC-1alpha has modifying effects on the pathogenic process in HD.