Somatic expansion of the Huntington's disease CAG repeat in the brain is associated with an earlier age of disease onset.

The age of onset of Huntington's disease (HD) is determined primarily by the length of the HD CAG repeat mutation, but is also influenced by other modifying factors. Delineating these modifiers is a critical step towards developing validated therapeutic targets in HD patients. The HD CAG repeat is somatically unstable, undergoing progressive length increases over time, particularly in brain regions that are the targets of neurodegeneration. Here, we have explored the hypothesis that somatic instability of the HD CAG repeat is itself a modifier of disease. Using small-pool PCR, we quantified somatic instability in the cortex region of the brain from a cohort of HD individuals exhibiting phenotypic extremes of young and old disease onset as predicted by the length of their constitutive HD CAG repeat lengths. After accounting for constitutive repeat length, somatic instability was found to be a significant predictor of onset age, with larger repeat length gains associated with earlier disease onset. These data are consistent with the hypothesis that somatic HD CAG repeat length expansions in target tissues contribute to the HD pathogenic process, and support pursuing factors that modify somatic instability as viable therapeutic targets.

[1]  Jane S. Paulsen,et al.  Evidence for a modifier of onset age in Huntington disease linked to the HD gene in 4p16 , 2004, Neurogenetics.

[2]  N. Bhattacharyya,et al.  Modulation of age at onset in Huntington's disease and spinocerebellar ataxia type 2 patients originated from eastern India , 2003, Neuroscience Letters.

[3]  A. Messer,et al.  Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice , 1999, Nature Genetics.

[4]  Harry T Orr,et al.  Regional differences of somatic CAG repeat instability do not account for selective neuronal vulnerability in a knock-in mouse model of SCA1. , 2003, Human molecular genetics.

[5]  P. Bauer,et al.  The S18Y polymorphism in the UCHL1 gene is a genetic modifier in Huntington’s disease , 2006, Neurogenetics.

[6]  D. Brock,et al.  A new polymerase chain reaction (PCR) assay for the trinucleotide repeat that is unstable and expanded on Huntington's disease chromosomes. , 1993, Molecular and cellular probes.

[7]  Harper Ps.  Huntington's disease: a clinical, genetic and molecular model for polyglutamine repeat disorders. , 1999 .

[8]  M. Hayden,et al.  The Gln-Ala repeat transcriptional activator CA150 interacts with huntingtin: neuropathologic and genetic evidence for a role in Huntington's disease pathogenesis. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[9]  Nahida Matta,et al.  CAG expansion affects the expression of mutant huntingtin in the Huntington's disease brain , 1995, Neuron.

[10]  R. Ferrante,et al.  Neuropathological Classification of Huntington's Disease , 1985, Journal of neuropathology and experimental neurology.

[11]  M. MacDonald,et al.  Huntington's disease. , 1995, Neuromolecular medicine.

[12]  J. Gusella,et al.  Huntington's disease. , 1995, Seminars in cell biology.

[13]  Joonil Jung,et al.  CREB-Binding Protein Modulates Repeat Instability in a Drosophila Model for PolyQ Disease , 2007, Science.

[14]  L. Tong,et al.  Huntingtin-associated protein-1 is a modifier of the age-at-onset of Huntington's disease. , 2008, Human molecular genetics.

[15]  M. Siciliano,et al.  Dramatic, expansion-biased, age-dependent, tissue-specific somatic mosaicism in a transgenic mouse model of triplet repeat instability. , 2000, Human molecular genetics.

[16]  S. Bidichandani,et al.  Analysis of unstable triplet repeats using small-pool polymerase chain reaction. , 2004, Methods in molecular biology.

[17]  P. Detloff,et al.  DNA instability in postmitotic neurons , 2008, Proceedings of the National Academy of Sciences.

[18]  Ehud Shapiro,et al.  A Universal Mechanism Ties Genotype to Phenotype in Trinucleotide Diseases , 2007, PLoS Comput. Biol..

[19]  L. Frati,et al.  DNA instability in replicating Huntington's disease lymphoblasts , 2009, BMC Medical Genetics.

[20]  S. Warren,et al.  Genetic instabilities and hereditary neurological diseases , 1998 .

[21]  C A Ross,et al.  Correlation between the onset age of Huntington's disease and length of the trinucleotide repeat in IT-15. , 1993, Human molecular genetics.

[22]  P. Shelbourne,et al.  Dramatic mutation instability in HD mouse striatum: does polyglutamine load contribute to cell-specific vulnerability in Huntington's disease? , 2000, Human molecular genetics.

[23]  Jane S. Paulsen,et al.  A genome scan for modifiers of age at onset in Huntington disease: The HD MAPS study. , 2003, American journal of human genetics.

[24]  Jane S. Paulsen,et al.  Genome-wide significance for a modifier of age at neurological onset in Huntington's Disease at 6q23-24: the HD MAPS study , 2006, BMC Medical Genetics.

[25]  M. MacDonald,et al.  Evidence for the GluR6 gene associated with younger onset age of Huntington’s disease , 1999, Neurology.

[26]  Wenya Linda Bi,et al.  Triplet repeat mutation length gains correlate with cell-type specific vulnerability in Huntington disease brain. , 2007, Human molecular genetics.

[27]  L. Cardon,et al.  Replication of twelve association studies for Huntington’s disease residual age of onset in large Venezuelan kindreds , 2006, Journal of Medical Genetics.

[28]  Tetsuo Ashizawa,et al.  Somatic instability of CTG repeat in myotonic dystrophy , 1993, Neurology.

[29]  A. Destée,et al.  Mutation analysis and association studies of the ubiquitin carboxy-terminal hydrolase L1 gene in Huntington's disease , 2002, Neuroscience Letters.

[30]  D. Monckton,et al.  Inherited CAG.CTG allele length is a major modifier of somatic mutation length variability in Huntington disease. , 2007, DNA repair.

[31]  M. MacDonald,et al.  Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington's disease , 1993, Nature Genetics.

[32]  H. Paulson,et al.  Genetic Instabilities and Hereditary Neurological Diseases , 1998 .

[33]  Bruce Fischl,et al.  Cerebral cortex and the clinical expression of Huntington's disease: complexity and heterogeneity. , 2008, Brain : a journal of neurology.

[34]  R. Roos,et al.  Somatic expansion of the (CAG)n repeat in Huntington disease brains , 1995, Human Genetics.

[35]  L. Cardon,et al.  Genomewide linkage scan reveals novel loci modifying age of onset of Huntington's disease in the Venezuelan HD kindreds , 2008, Genetic epidemiology.

[36]  G Norbury,et al.  Genotypes at the GluR6 kainate receptor locus are associated with variation in the age of onset of Huntington disease. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[37]  Arne Klungland,et al.  OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells , 2007, Nature.

[38]  Jacqueline K. White,et al.  Length-dependent gametic CAG repeat instability in the Huntington's disease knock-in mouse. , 1999, Human molecular genetics.

[39]  Raju Kucherlapati,et al.  (CAG)n-hairpin DNA binds to Msh2–Msh3 and changes properties of mismatch recognition , 2005, Nature Structural &Molecular Biology.

[40]  Jane S. Paulsen,et al.  Detection of Huntington’s disease decades before diagnosis: the Predict-HD study , 2007, Journal of Neurology, Neurosurgery, and Psychiatry.

[41]  Manish S. Shah,et al.  A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes , 1993, Cell.

[42]  Edith T. Lopez,et al.  Intergenerational and striatal CAG repeat instability in Huntington's disease knock-in mice involve different DNA repair genes , 2009, Neurobiology of Disease.

[43]  Elizabeth Evans,et al.  Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis. , 2003, Human molecular genetics.

[44]  M. MacDonald,et al.  Mismatch repair gene Msh2 modifies the timing of early disease in Hdh(Q111) striatum. , 2003, Human molecular genetics.

[45]  D. Le Gall,et al.  Cognitive changes in asymptomatic carriers of the Huntington disease mutation gene , 2007, European journal of neurology.

[46]  M. Hayden,et al.  Somatic and gonadal mosaicism of the Huntington disease gene CAG repeat in brain and sperm , 1994, Nature Genetics.

[47]  M. Hayden,et al.  The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease , 1993, Nature Genetics.

[48]  Karen Marder,et al.  Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[49]  J. Penney,et al.  Trinucleotide repeat length instability and age of onset in Huntington's disease , 1993, Nature Genetics.