RGD Reference Report - ASK1 and MAP2K6 as modifiers of age at onset in Huntington's disease. - Rat Genome Database

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ASK1 and MAP2K6 as modifiers of age at onset in Huntington's disease.

Authors: Arning, L  Monte, D  Hansen, W  Wieczorek, S  Jagiello, P  Akkad, DA  Andrich, J  Kraus, PH  Saft, C  Epplen, JT 
Citation: Arning L, etal., J Mol Med (Berl). 2008 Apr;86(4):485-90. doi: 10.1007/s00109-007-0299-6. Epub 2008 Mar 8.
RGD ID: 10412314
Pubmed: PMID:18327563   (View Abstract at PubMed)
DOI: DOI:10.1007/s00109-007-0299-6   (Journal Full-text)

Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disease associated with abnormal expansions of a stretch of perfect CAG repeats in the HD gene. The number of repeat units is predictive for the age at onset (AO) of neurological symptoms. Part of the remaining variation in AO is attributed to modifier genes. In this study, genes involved in apoptosis were investigated as candidates for modulating AO in HD. A panel of 304 candidate genes was screened for allelic associations with motor AO via linked micro-satellite markers by pooling the DNAs of HD individuals from opposite ends of the AO distribution. After genotyping promising markers from the pooling experiment individually, markers revealed consolidated evidence for association in a candidate region comprising the genes MAP3K5 (ASK1)/PEX7 at 6q23.3 and in the gene MAP2K6 at 17q24.3. Fine-mapping of these candidate regions in a cohort of 250 Caucasian HD patients using single nucleotide polymorphism (SNP) markers delimitated the precise locations of association. Certain variations in an ASK1-PEX7 haplotype block explain 2.6% of additional variance in AO in our HD cohort. In males, 4.9% additional variance could be attributed to MAP2K6 genotype variations. Altogether, ASK1-PEX7 haplotypes and MAP2K2 genotype variations explain 6.3% additional variance in AO for HD. We hypothesise that sequence variations of ASK1 and MAP2K6 lead to partially sex-specific changes in the levels and/or phosphorylation states of p38 and p38-regulated proteins that might contribute to the observed delaying effects in the AO of HD.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Huntington's disease onsetIAGP 10412314DNa:SNO:promoter:rs5880308(human)RGD 
Huntington's disease onsetISOMAP3K5 (Homo sapiens)10412314; 10412314DNa:SNO:promoter:rs5880308(human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Map3k5  (mitogen-activated protein kinase kinase kinase 5)

Genes (Mus musculus)
Map3k5  (mitogen-activated protein kinase kinase kinase 5)

Genes (Homo sapiens)
MAP3K5  (mitogen-activated protein kinase kinase kinase 5)


Additional Information