Abstract
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.
References
The Huntington’s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72:971–983
Wieczorek S, Epplen JT (2006) Huntington’s disease. In: Ganten D, Ruckpaul K (eds) Encyclopedic reference of genomics and proteomics in molecular medicine. Springer, Berlin
Myers RH, Vonsattel JP, Paskevich PA, Kiely DK, Stevens TJ, Cupples LA, Richardson EP, Bird ED (1991) Decreased neuronal and increased oligodendroglial densities in Huntington’s disease caudate nucleus. J Neuropathol Exp Neurol 50:729–742
Snell RG, MacMillan JC, Cheadle JP, Fenton I, Lazarou LP, Davies P, MacDonald ME, Gusella JF, Harper PS, Shaw DJ (1993) Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington’s disease. Nat Genet 4:393–397
Andrew SE, Goldberg YP, Kremer B, Telenius H, Theilmann J, Adam S, Starr E, Squitieri F, Lin B, Kalchman MA et al (1993) The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington’s disease. Nat Genet 4:398–403
Duyao M, Ambrose C, Myers R, Novelletto A, Persichetti F, Frontali M, Folstein S, Ross C, Franz M, Abbott M et al (1993) Trinucleotide repeat length instability and age of onset in Huntington’s disease. Nat Genet 4:387–392
Kehoe P, Krawczak M, Harper PS, Owen MJ, Jones AL (1999) Age of onset in Huntington disease: sex specific influence of apolipoprotein E genotype and normal CAG repeat length. J Med Genet 36:108–111
The U.S.–Venezuela Collaborative Research Project, Wexler NS (2004) Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington’s disease age of onset. Proc Natl Acad Sci U S A 101:3498–3503
Andresen JM, Gayan J, Cherny SS, Brocklebank D, Alkorta-Aranburu G, Addis EA, Cardon LR, Housman DE, Wexler NS (2007) Replication of twelve association studies for Huntington’s disease residual age of onset in large Venezuelan kindreds. J Med Genet 44:44–50
Arning L, Kraus PH, Valentin S, Saft C, Epplen JT (2005) NR2A and NR2B receptor gene variations modify age at onset in Huntington disease. Neurogenetics 6:25–28
Arning L, Saft C, Wieczorek, S, Andrich, J, Kraus PH, Epplen JT (2007) NR2A and NR2B receptor gene variations modify age at onset in Huntington disease in a sex-specific manner. Hum Genet 122:175–182
Li JL, Hayden MR, Almqvist EW, Brinkman RR, Durr A, Dode C, Morrison PJ, Suchowersky O, Ross CA, Margolis RL, Rosenblatt A, Gomez-Tortosa E, Cabrero DM, Novelletto A, Frontali M, Nance M, Trent RJ, McCusker E, Jones R, Paulsen JS, Harrison M, Zanko A, Abramson RK, Russ AL, Knowlton B, Djousse L, Mysore JS, Tariot S, Gusella MF, Wheeler VC, Atwood LD, Cupples LA, Saint-Hilaire M, Cha JH, Hersch SM, Koroshetz WJ, Gusella JF, MacDonald ME, Myers RH (2003) A genome scan for modifiers of age at onset in Huntington disease: The HD MAPS study. Am J Hum Genet 73:682–687
Li JL, Hayden MR, Warby SC, Durr A, Morrison PJ, Nance M, Ross CA, Margolis RL, Rosenblatt A, Squitieri F, Frati L, Gomez-Tortosa E, Garcia CA, Suchowersky O, Klimek ML, Trent RJ, McCusker E, Novelletto A, Frontali M, Paulsen JS, Jones R, Ashizawa T, Lazzarini A, Wheeler VC, Prakash R, Xu G, Djousse L, Mysore JS, Gillis T, Hakky M, Cupples LA, Saint-Hilaire MH, Cha JH, Hersch SM, Penney JB, Harrison MB, Perlman SL, Zanko A, Abramson RK, Lechich AJ, Duckett A, Marder K, Conneally PM, Gusella JF, MacDonald ME, Myers RH (2006) Genome-wide significance for a modifier of age at neurological onset in Huntington’s disease at 6q23–24: the HD MAPS study. BMC Med Genet 7:71
Hickey MA, Chesselet MF (2003) Apoptosis in Huntington’s disease. Prog Neuro-psychopharmacol Biol Psychiatry 2:255–265
Kim YJ, Yi Y, Sapp E, Wang Y, Cuiffo B, Kegel KB, Qin ZH, Aronin N, DiFiglia M (2001) Caspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington’s dise brains, associate with membranes, and undergo calpain-dependent proteolysis. Proc Natl Acad Sci U S A 22:12784–12789
Johnson GL, Lapadat R (2002) Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298:1911–1912
Jagiello P, Gencik M, Arning L, Wieczorek S, Kunstmann E, Csernok E, Gross WL, Epplen JT (2004) New genomic region for Wegener’s granulomatosis as revealed by an extended association screen with 202 apoptosis-related genes. Hum Genet 114:468–477
Wieczorek S, Jagiello P, Arning L, Dahmen N, Epplen JT (2004) Screening for candidate gene regions in narcolepsy using a microsatellite based approach and pooled DNA. J Mol Med 82:696–705
Braverman N, Chen L, Lin P, Obie C, Steel G, Douglas P, Chakraborty PK, Clarke JT, Boneh A, Moser A, Moser H, Valle D (2002) Mutation analysis of PEX7 in 60 probands with rhizomelic chondrodysplasia punctata and functional correlations of genotype with phenotype. Human Mutat 20:284–297
Weston CR, Lambright DG, Davis RJ (2002) Signal transduction. MAP kinase signaling specificity. Science 296:2345–2347
Nagai H, Noguchi T, Takeda K, Ichijo H (2007) Pathophysiological roles of ASK1-MAP kinase signaling pathways. J Biochem Mol Biol 40:1–6
Liu YF (1998) Expression of polyglutamine-expanded Huntingtin activates the SEK1-JNK pathway and induces apoptosis in a hippocampal neuronal cell line. J Biol Chem 273:28873–28877
Nishitoh H, Matsuzawa A, Tobiume K, Saegusa K, Takeda K, Inoue K, Hori S, Kakizuka A, Ichijo H (2002) ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev 16:1345–1355
Werner T (2000) Computer-assisted analysis of transcription control regions. Matinspector and other programs. Methods Mol Biol 132:337–349
Kherrouche Z, Blais A, Ferreira E, De Launoit Y, Monté D (2006) ASK-1 (apoptosis signal-regulating kinase 1) is a direct E2F target gene. Biochem J 396:547–556
Angele MK, Nitsch S, Knoferl MW, Ayala A, Angele P, Schildberg FW, Jauch KW, Chaudry IH (2003) Sex-specific p38 MAP kinase activation following trauma-hemorrhage: involvement of testosterone and estradiol. Am J Physiol Endocrinol Metab 285:189–196
Imahara SD, Jelacic S, Junker CE, O, Keefe GE (2005) The influence of gender on human innate immunity. Surgery 138:275–282
Acknowledgments
We thank Maren Mai for the technical help. This work was supported by FoRUM grant 821984.
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Arning, L., Monté, D., Hansen, W. et al. ASK1 and MAP2K6 as modifiers of age at onset in Huntington’s disease. J Mol Med 86, 485–490 (2008). https://doi.org/10.1007/s00109-007-0299-6
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DOI: https://doi.org/10.1007/s00109-007-0299-6