Exome sequencing of individuals with Huntington's disease implicates FAN1 nuclease activity in slowing CAG expansion and disease onset.

The age at onset of motor symptoms in Huntington's disease (HD) is driven by HTT CAG repeat length but modified by other genes. In this study, we used exome sequencing of 683 patients with HD with extremes of onset or phenotype relative to CAG length to identify rare variants associated with clinical effect. We discovered damaging coding variants in candidate modifier genes identified in previous genome-wide association studies associated with altered HD onset or severity.

Similar striatal gene expression profiles in the striatum of the YAC128 and HdhQ150 mouse models of Huntington's disease are not reflected in mutant Huntingtin inclusion prevalence.

Background: The YAC128 model of Huntington's disease (HD) shows substantial deficits in motor, learning and memory tasks and alterations in its transcriptional profile. We examined the changes in the transcriptional profile in the YAC128 mouse model of HD at 6, 12 and 18 months and compared these with those seen in other models and human HD caudate.

Results: Differential gene expression by genotype showed that genes related to neuronal function, projection outgrowth and cell adhesion were altered in expression.

Huntingtin Exists as Multiple Splice Forms in Human Brain.

Background: A CAG repeat expansion in HTT has been known to cause Huntington's disease for over 20 years. The genomic sequence of the 67 exon HTT is clear but few reports have detailed alternative splicing or alternative transcripts. Most eukaryotic genes with multiple exons show alternative splicing that increases the diversity of the transcriptome and proteome: it would be surprising if a gene with 67 known exons in its two major transcripts did not present some alternative transcripts.

Identification of novel alternative splicing events in the huntingtin gene and assessment of the functional consequences using structural protein homology modelling.

Huntington's disease (HD) is an inherited progressive neurodegenerative disorder caused by a pathological CAG trinucleotide repeat expansion in the large multi-exon gene, huntingtin (HTT). Although multiple pathogenic mechanisms have been proposed for HD, there is increasing interest in the RNA processing of the HTT gene. In mammals, most multi-exon genes are alternatively spliced; however, few alternative transcripts have been described for HTT.

MAP kinase phosphatase 1 (MKP-1/DUSP1) is neuroprotective in Huntington's disease via additive effects of JNK and p38 inhibition.

We previously demonstrated that sodium butyrate is neuroprotective in Huntington's disease (HD) mice and that this therapeutic effect is associated with increased expression of mitogen-activated protein kinase/dual-specificity phosphatase 1 (MKP-1/DUSP1). Here we show that enhancing MKP-1 expression is sufficient to achieve neuroprotection in lentiviral models of HD. Wild-type MKP-1 overexpression inhibited apoptosis in primary striatal neurons exposed to an N-terminal fragment of polyglutamine-expanded huntingtin (Htt171-82Q), blocking caspase-3 activation and significantly reducing neuronal cell death.

Longitudinal analysis of gene expression and behaviour in the HdhQ150 mouse model of Huntington's disease.

Substantial transcriptional changes are seen in Huntington's disease (HD) brain and parallel early changes in gene expression are observed in mouse models of HD. Analysis of behaviour in such models also shows substantial deficits in motor, learning and memory tasks. We examined the changes in the transcriptional profile in the HdhQ150 mouse model of HD at 6, 12 and 18 months and correlated these changes with the behavioural tasks the animals had undertaken.

Cis- and trans- loci influence expression of the schizophrenia susceptibility gene DTNBP1.

Susceptibility to complex disease appears to be partly mediated by heritable differences in gene expression. Where cis-acting effects on a gene's expression influence disease susceptibility, other genes containing polymorphism with a trans-acting effect on expression of that gene may also be expected to modulate risk. Use of the expression of an identified disease gene as an endophenotype for quantitative linkage analysis may therefore provide a powerful method for mapping loci that modulate disease susceptibility.

Brain gene expression correlates with changes in behavior in the R6/1 mouse model of Huntington's disease.

Huntington's disease (HD) is an inherited neurodegeneration that causes a severe progressive illness and early death. Several animal models of the disease have been generated carrying the causative mutation and these have shown that one of the earliest molecular signs of the disease process is a substantial transcriptional deficit. We examined the alterations in brain gene expression in the R6/1 mouse line over the course of the development of phenotypic signs from 18 to 27 weeks.

Regional and cellular gene expression changes in human Huntington's disease brain.

Huntington's disease (HD) pathology is well understood at a histological level but a comprehensive molecular analysis of the effect of the disease in the human brain has not previously been available. To elucidate the molecular phenotype of HD on a genome-wide scale, we compared mRNA profiles from 44 human HD brains with those from 36 unaffected controls using microarray analysis. Four brain regions were analyzed: caudate nucleus, cerebellum, prefrontal association cortex [Brodmann's area 9 (BA9)] and motor cortex [Brodmann's area 4 (BA4)].

Molecular analysis of the genotype-phenotype relationship in factor X deficiency.

Factor X deficiency is a rare haemorrhagic condition, normally inherited as an autosomal recessive trait, in which a variable clinical presentation correlates poorly with laboratory phenotype. The factor X (F10) genes of 14 unrelated individuals with factor X deficiency (12 familial and two sporadic cases) were sequenced yielding a total of 13 novel mutations. Family studies were performed in order to distinguish the contributions of individual mutant F10 alleles to the clinical and laboratory phenotypes.