Bio

Professional Education


  • Doctor of Philosophy, University of British Columbia, Neuroscience (2007)
  • Bachelor of Science, University of Victoria, Biology (1998)
  • Bachelor of Science, University of Victoria, Psychology (1998)

Stanford Advisors


Research & Scholarship

Current Research and Scholarly Interests


My research is focused on the genetics of sleep and understanding its relationship to neurological disease.

The brain generates complex patterns of electrical activity that can be measured by electroencephalography (EEG) and thought of as an 'EEG fingerprint' that is unique to individuals. The EEG fingerprint is particularly evident during sleep, when brain activity is generated in the absence of consciousness and sensory inputs. I am interested in genes that regulate the brain circuitry and neurochemistry that generates this EEG fingerprint.

By refining techniques for EEG analysis of human sleep data, we are exploring how variations in the genome influence differences in brain activity during sleep. Many micro-architectural features of EEG activity, such as sleep spindles and k-complexes, are heritable and trait-like. Specific patterns of the EEG fingerprint are altered early in the progression of certain neurodegenerative diseases, such as Huntington disease and Parkinson disease, as well as psychiatric conditions that are associated with sleep disorders, such as depression and schizophrenia.

These stable traits in the EEG fingerprint are endophenotypes - biomarkers of disease with a clear genetic basis - and can lead to a better understanding of the neurobiological basis of sleep and neurological disorders.

Publications

Journal Articles


  • Nocturnal Intermittent Hypoxia Is Independently Associated with Pain in Subjects Suffering from Sleep-disordered Breathing. Anesthesiology Doufas, A. G., Tian, L., Davies, M. F., Warby, S. C. 2013; 119 (5): 1149-1162

    Abstract

    On the basis of experimental and clinical evidence, the authors hypothesized that nocturnal hypoxemia would be associated with pain reports in subjects suffering from sleep-disordered breathing, independently of sleep fragmentation and inflammation.After obtaining institutional approval and access to the Cleveland Family Study phenotype and genotype data, the authors used proportional odds regression to examine the association between arterial desaturation and four different types of pain, as well as their composite measure, sequentially adjusted for: (1) clinical characteristics and (2) sleep fragmentation and inflammation. The authors also examined the association of selected candidate single-nucleotide polymorphisms with pain reports.Decreased minimum nocturnal arterial saturation increased the odds for morning headache (adjusted odds ratio per SD=1.36; 95% CI [1.08-1.71]; P=0.009), headache disrupting sleep (1.29 [1.10-1.51]; P=0.002), and chest pain while in bed (1.37 [1.10-1.70]; P=0.004). A decrease in the minimum nocturnal saturation from 92 to 75% approximately doubled the odds for pain. One single-nucleotide polymorphism for the α 1 chain of collagen type XI (COL11A1-rs1676486) gene was significantly associated with headache disrupting sleep (odds ratio=1.72 [1.01-2.94]; P=0.038), pain disrupting sleep (odds ratio=1.85 [1.04-3.28]; P=0.018), and pain composite (odds ratio=1.89 [1.14-3.14]; P=0.001).Nocturnal arterial desaturation may be associated with an increased pain in subjects with sleep-disordered breathing, independently of sleep fragmentation and inflammation.

    View details for DOI 10.1097/ALN.0b013e3182a951fc

    View details for PubMedID 24025612

  • A fully humanized transgenic mouse model of Huntington disease HUMAN MOLECULAR GENETICS Southwell, A. L., Warby, S. C., Carroll, J. B., Doty, C. N., Skotte, N. H., Zhang, W., Villanueva, E. B., Kovalik, V., Xie, Y., Pouladi, M. A., Collins, J. A., Yang, X. W., Franciosi, S., Hayden, M. R. 2013; 22 (1): 18-34

    Abstract

    Silencing the mutant huntingtin gene (muHTT) is a direct and simple therapeutic strategy for the treatment of Huntington disease (HD) in principle. However, targeting the HD mutation presents challenges because it is an expansion of a common genetic element (a CAG tract) that is found throughout the genome. Moreover, the HTT protein is important for neuronal health throughout life, and silencing strategies that also reduce the wild-type HTT allele may not be well tolerated during the long-term treatment of HD. Several HTT silencing strategies are in development that target genetic sites in HTT that are outside of the CAG expansion, including HD mutation-linked single-nucleotide polymorphisms and the HTT promoter. Preclinical testing of these genetic therapies has required the development of a new mouse model of HD that carries these human-specific genetic targets. To generate a fully humanized mouse model of HD, we have cross-bred BACHD and YAC18 on the Hdh(-/-) background. The resulting line, Hu97/18, is the first murine model of HD that fully genetically recapitulates human HD having two human HTT genes, no mouse Hdh genes and heterozygosity of the HD mutation. We find that Hu97/18 mice display many of the behavioral changes associated with HD including motor, psychiatric and cognitive deficits, as well as canonical neuropathological abnormalities. This mouse line will be useful for gaining additional insights into the disease mechanisms of HD as well as for testing genetic therapies targeting human HTT.

    View details for DOI 10.1093/hmg/dds397

    View details for Web of Science ID 000312643400002

    View details for PubMedID 23001568

  • Determinants of Cortical Synchrony SLEEP Mongrain, V., Warby, S. C. 2012; 35 (3): 309-310

    View details for DOI 10.5665/sleep.1680

    View details for Web of Science ID 000300950400002

    View details for PubMedID 22379234

  • CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion NEUROLOGY Lee, J., Ramos, E. M., Lee, J., Gillis, T., Mysore, J. S., Hayden, M. R., Warby, S. C., Morrison, P., Nance, M., Ross, C. A., Margolis, R. L., Squitieri, F., Orobello, S., Di Donato, S., Gomez-Tortosa, E., Ayuso, C., Suchowersky, O., Trent, R. J., McCusker, E., Novelletto, A., Frontali, M., Jones, R., Ashizawa, T., Frank, S., Saint-Hilaire, M. H., Hersch, S. M., Rosas, H. D., Lucente, D., Harrison, M. B., Zanko, A., Abramson, R. K., Marder, K., Sequeiros, J., Paulsen, J. S., Landwehrmeyer, G. B., Myers, R. H., MacDonald, M. E., Gusella, J. F. 2012; 78 (10): 690-695

    Abstract

    Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs.We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression.An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele.Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors.

    View details for DOI 10.1212/WNL.0b013e318249f683

    View details for Web of Science ID 000301236400004

    View details for PubMedID 22323755

  • Potent and Selective Antisense Oligonucleotides Targeting Single-Nucleotide Polymorphisms in the Huntington Disease Gene/Allele-Specific Silencing of Mutant Huntingtin MOLECULAR THERAPY Carroll, J. B., Warby, S. C., Southwell, A. L., Doty, C. N., Greenlee, S., Skotte, N., Hung, G., Bennett, C. F., Freier, S. M., Hayden, M. R. 2011; 19 (12): 2178-2185

    Abstract

    Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG-expansion in the huntingtin gene (HTT) that results in a toxic gain of function in the mutant huntingtin protein (mHTT). Reducing the expression of mHTT is therefore an attractive therapy for HD. However, wild-type HTT protein is essential for development and has critical roles in maintaining neuronal health. Therapies for HD that reduce wild-type HTT may therefore generate unintended negative consequences. We have identified single-nucleotide polymorphism (SNP) targets in the human HD population for the disease-specific targeting of the HTT gene. Using primary cells from patients with HD and the transgenic YAC18 and BACHD mouse lines, we developed antisense oligonucleotide (ASO) molecules that potently and selectively silence mHTT at both exonic and intronic SNP sites. Modification of these ASOs with S-constrained-ethyl (cET) motifs significantly improves potency while maintaining allele selectively in vitro. The developed ASO is potent and selective for mHTT in vivo after delivery to the mouse brain. We demonstrate that potent and selective allele-specific knockdown of the mHTT protein can be achieved at therapeutically relevant SNP sites using ASOs in vitro and in vivo.

    View details for DOI 10.1038/mt.2011.201

    View details for Web of Science ID 000298039300012

    View details for PubMedID 21971427

  • Narcolepsy Onset Is Seasonal and Increased following the 2009 H1N1 Pandemic in China ANNALS OF NEUROLOGY Han, F., Lin, L., Warby, S. C., Faraco, J., Li, J., Dong, S. X., An, P., Zhao, L., Wang, L. H., Li, Q. Y., Yan, H., Gao, Z. C., Yuan, Y., Strohl, K. P., Mignot, E. 2011; 70 (3): 410-417

    Abstract

    Narcolepsy is caused by the loss of hypocretin/orexin neurons in the hypothalamus, which is likely the result of an autoimmune process. Recently, concern has been raised over reports of narcolepsy in northern Europe following H1N1 vaccination.The study is a retrospective analysis of narcolepsy onset in subjects diagnosed in Beijing, China (1998-2010). Self-reported month and year of onset were collected from 629 patients (86% children). Graphical presentation, autocorrelations, chi-square, and Fourier analysis were used to assess monthly variation in onset. Finally, 182 patients having developed narcolepsy after October 2009 were asked for vaccination history.The occurrence of narcolepsy onset was seasonal, significantly influenced by month and calendar year. Onset was least frequent in November and most frequent in April, with a 6.7-fold increase from trough to peak. Studying year-to-year variation, we found a 3-fold increase in narcolepsy onset following the 2009 H1N1 winter influenza pandemic. The increase is unlikely to be explained by increased vaccination, as only 8 of 142 (5.6%) patients recalled receiving an H1N1 vaccination. Cross-correlation indicated a significant 5- to 7-month delay between the seasonal peak in influenza/cold or H1N1 infections and peak in narcolepsy onset occurrences.In China, narcolepsy onset is highly correlated with seasonal and annual patterns of upper airway infections, including H1N1 influenza. In 2010, the peak seasonal onset of narcolepsy was phase delayed by 6 months relative to winter H1N1 infections, and the correlation was independent of H1N1 vaccination in the majority of the sample.

    View details for DOI 10.1002/ana.22587

    View details for Web of Science ID 000294816800014

    View details for PubMedID 21866560

  • HTT haplotypes contribute to differences in Huntington disease prevalence between Europe and East Asia EUROPEAN JOURNAL OF HUMAN GENETICS Warby, S. C., Visscher, H., Collins, J. A., Doty, C. N., Carter, C., Butland, S. L., Hayden, A. R., Kanazawa, I., Ross, C. J., Hayden, M. R. 2011; 19 (5): 561-566

    Abstract

    Huntington disease (HD) results from CAG expansion in the huntingtin (HTT) gene. Although HD occurs worldwide, there are large geographic differences in its prevalence. The prevalence in populations derived from Europe is 10-100 times greater than in East Asia. The European general population chromosomes can be grouped into three major haplogroups (group of similar haplotypes): A, B and C. The majority of HD chromosomes in Europe are found on haplogroup A. However, in the East-Asian populations of China and Japan, we find the majority of HD chromosomes are associated with haplogroup C. The highest risk HD haplotypes (A1 and A2), are absent from the general and HD populations of China and Japan, and therefore provide an explanation for why HD prevalence is low in East Asia. Interestingly, both East-Asian and European populations share a similar low level of HD on haplogroup C. Our data are consistent with the hypothesis that different HTT haplotypes have different mutation rates, and geographic differences in HTT haplotypes explain the difference in HD prevalence. Further, the bias for expansion on haplogroup C in the East-Asian population cannot be explained by a higher average CAG size, as haplogroup C has a lower average CAG size in the general East-Asian population compared with other haplogroups. This finding suggests that CAG-tract size is not the only factor important for CAG instability. Instead, the expansion bias may be because of genetic cis-elements within the haplotype that influence CAG instability in HTT, possibly through different mutational mechanisms for the different haplogroups.

    View details for DOI 10.1038/ejhg.2010.229

    View details for Web of Science ID 000289789500015

    View details for PubMedID 21248742

  • Common variants in P2RY11 are associated with narcolepsy NATURE GENETICS Kornum, B. R., Kawashima, M., Faraco, J., Lin, L., Rico, T. J., Hesselson, S., Axtell, R. C., Kuipers, H., Weiner, K., Hamacher, A., Kassack, M. U., Han, F., Knudsen, S., Li, J., Dong, X., Winkelmann, J., Plazzi, G., Nevsimalova, S., Hong, S., Honda, Y., Honda, M., Hogl, B., Ton, T. G., Montplaisir, J., Bourgin, P., Kemlink, D., Huang, Y., Warby, S., Einen, M., Eshragh, J. L., Miyagawa, T., Desautels, A., Ruppert, E., Hesla, P. E., Poli, F., Pizza, F., Frauscher, B., Jeong, J., Lee, S., Strohl, K. P., Longstreth, W. T., Kvale, M., Dobrovolna, M., Ohayon, M. M., Nepom, G. T., Wichmann, H., Rouleau, G. A., Gieger, C., Levinson, D. F., Gejman, P. V., Meitinger, T., Peppard, P., Young, T., Jennum, P., Steinman, L., Tokunaga, K., Kwok, P., Risch, N., Hallmayer, J., Mignot, E. 2011; 43 (1): 66-U90

    Abstract

    Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genome-wide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3' untranslated region of P2RY11, the purinergic receptor subtype P2Y?? gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 × 10?¹?, odds ratio = 1.28, 95% CI 1.19-1.39, n = 5689). The disease-associated allele is correlated with reduced expression of P2RY11 in CD8(+) T lymphocytes (339% reduced, P = 0.003) and natural killer (NK) cells (P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases.

    View details for DOI 10.1038/ng.734

    View details for Web of Science ID 000285683500018

    View details for PubMedID 21170044

  • Huntington Disease GeneReviews Warby SC, Graham RK, Hayden MR 2010
  • Response to Falush: a role for cis-element polymorphisms in HD. American journal of human genetics Warby, S. C., Visscher, H., Butland, S., Pearson, C. E., Hayden, M. R. 2009; 85 (6): 942-945

    View details for DOI 10.1016/j.ajhg.2009.11.006

    View details for PubMedID 20004773

  • CAG Expansion in the Huntington Disease Gene Is Associated with a Specific and Targetable Predisposing Haplogroup AMERICAN JOURNAL OF HUMAN GENETICS Warby, S. C., Montpetit, A., Hayden, A. R., Carroll, J. B., Butland, S. L., Visscher, F., Collins, J. A., Semaka, A., Hudson, T. J., Hayden, M. R. 2009; 84 (3): 351-366

    Abstract

    Huntington disease (HD) is an autosomal-dominant disorder that results from >or=36 CAG repeats in the HD gene (HTT). Approximately 10% of patients inherit a chromosome that underwent CAG expansion from an unaffected parent with <36 CAG repeats. This study is a comprehensive analysis of genetic diversity in HTT and reveals that HD patients of European origin (n = 65) have a significant enrichment (95%) of a specific set of 22 tagging single nucleotide polymorphisms (SNPs) that constitute a single haplogroup. The disease association of many SNPs is much stronger than any previously reported polymorphism and was confirmed in a replication cohort (n = 203). Importantly, the same haplogroup is also significantly enriched (83%) in individuals with 27-35 CAG repeats (intermediate alleles, n = 66), who are unaffected by the disease, but have increased CAG tract sizes relative to the general population (n = 116). These data support a stepwise model for CAG expansion into the affected range (>or=36 CAG) and identifies specific haplogroup variants in the general population associated with this instability. The specific variants at risk for CAG expansion are not present in the general population in China, Japan, and Nigeria where the prevalence of HD is much lower. The current data argue that cis-elements have a major predisposing influence on CAG instability in HTT. The strong association between specific SNP alleles and CAG expansion also provides an opportunity of personalized therapeutics in HD where the clinical development of only a small number of allele-specific targets may be sufficient to treat up to 88% of the HD patient population.

    View details for DOI 10.1010/j.ajhg.2009.02.003

    View details for Web of Science ID 000264304200006

    View details for PubMedID 19249009

  • A prickly cause of progressive myoclonic epilepsy CLINICAL GENETICS Warby, S., Doty, C. N. 2009; 75 (3): 225-226
  • Phosphorylation of huntingtin reduces the accumulation of its nuclear fragments MOLECULAR AND CELLULAR NEUROSCIENCE Warby, S. C., Doty, C. N., Graham, R. K., Shively, J., Singaraja, R. R., Hayden, M. R. 2009; 40 (2): 121-127

    Abstract

    Huntingtin is phosphorylated on serine-421 (S421) by the pro-survival signaling protein kinases Akt and SGK. Phosphorylation of huntingtin at S421 is variable in different regions of the brain with the lowest levels observed in the striatum, which is further reduced by the mutation for Huntington disease (HD). Cleavage of huntingtin by caspase-6 at amino acid 586 is a crucial event in the pathogenesis of HD. Nuclear localization of huntingtin is also an important marker of HD and preventing or delaying its nuclear accumulation is protective in disease models. Phosphorylation influences proteolysis and clearance of many protein substrates. We therefore sought to investigate the influence of huntingtin phosphorylation at S421 on the accumulation of huntingtin-caspase-6 fragments because these fragments are generated in the nucleus and are crucial for the disease phenotype. Using phospho-huntingtin mutants and a cleavage site-specific neo-epitope huntingtin antibody, we demonstrate that phosphorylation at S421 reduces the nuclear accumulation of huntingtin-caspase-6 fragments by reducing huntingtin cleavage by caspase-6, the levels of full-length huntingtin, and its nuclear localization.

    View details for DOI 10.1016/j.mcn.2008.09.007

    View details for Web of Science ID 000263405800001

    View details for PubMedID 18992820

  • Re: Autopsy-proven Huntington's disease with 29 trinucleotide repeats MOVEMENT DISORDERS Semaka, A., Warby, S., Leavit, B. R., Hayden, M. R. 2008; 23 (12): 1794-1795

    View details for DOI 10.1002/mds.21820

    View details for Web of Science ID 000259767500031

    View details for PubMedID 18548612

  • Activated caspase-6 and caspase-6-cleaved fragments of huntingtin specifically colocalize in the nucleus HUMAN MOLECULAR GENETICS Warby, S. C., Doty, C. N., Graham, R. K., Carroll, J. B., Yang, Y., Singaraja, R. R., Overall, C. M., Hayden, M. R. 2008; 17 (15): 2390-2404

    Abstract

    Proteolysis of mutant huntingtin is crucial to the development of Huntington disease (HD). Specifically preventing proteolysis at the capase-6 (C6) consensus sequence at amino acid 586 of mutant huntingtin prevents the development of behavioural, motor and neuropathological features in a mouse model of HD. However, the mechanism underlying the selective toxicity of the 586 amino acid cleavage event is currently unknown. We have examined the subcellular localization of different caspase proteolytic fragments of huntingtin using neo-epitope antibodies. Our data suggest that the nucleus is the primary site of htt cleavage at amino acid 586. Endogenously cleaved 586 amino acid fragments are enriched in the nucleus of immortalized striatal cells and primary striatal neurons where they co-localize with active C6. Cell stress induced by staurosporine results in the nuclear translocation and activation of C6 and an increase in 586 amino acid fragments of huntingtin in the nucleus. In comparison, endogenous caspase-2/3-generated huntingtin 552 amino acid fragments localize to the perinuclear region. The different cellular itineraries of endogenously generated caspase products of huntingtin may provide an explanation for the selective toxicity of huntingtin fragments cleaved at amino acid 586.

    View details for DOI 10.1093/hmg/ddn139

    View details for Web of Science ID 000257788300014

    View details for PubMedID 18445618

  • Selective degeneration in YAC mouse models of Huntington disease BRAIN RESEARCH BULLETIN Van Raamsdonk, J. M., Warby, S. C., Hayden, M. R. 2007; 72 (2-3): 124-131

    Abstract

    Huntington disease (HD) is one of at least nine polyglutamine disorders caused by a CAG expansion in the coding region of a disease-causing gene. These disorders are characterized by selective degeneration of different regions of the brain, which is not explained by the expression pattern of the mutant protein. In HD, degeneration primarily occurs in the striatum and cortex. To examine the mechanisms responsible for the selective neuronal loss in HD, we have generated yeast artificial chromosome (YAC) transgenic models of HD that express full length mutant huntingtin (htt) from a YAC. These mice have appropriate tissue-specific and temporal expression of mutant htt and accordingly recapitulate the motor deficits, cognitive impairment and selective degeneration of HD. As in human patients, mutant htt expression is not increased in the affected regions of the brain. In contrast, detection of mutant htt in the nucleus is earliest and greatest in the striatum, the region most affected in HD, suggesting that selective nuclear localization of mutant htt may contribute to the region specific atrophy in these mice. Selective phosphorylation of mutant htt on serine 421 may also contribute, as phosphorylation of mutant htt reduces its toxicity and is decreased in the striatum compared to other regions of the brain. Finally, the fact that mutant htt expression increases the susceptibility of striatal neurons to excitotoxicity but not neurons from the cerebellum, suggests that altered sensitization to excitotoxic death may also contribute to selective degeneration in YAC mice. Overall, YAC mice recapitulate the region specific damage that occurs in HD and provide a suitable model for examining the mechanisms underlying of selective degeneration.

    View details for DOI 10.1016/j.brainresbull.2006.10.018

    View details for Web of Science ID 000245621000008

    View details for PubMedID 17352936

  • Brain-derived neurotrophic factor does not influence age at neurologic onset of Huntington's disease NEUROBIOLOGY OF DISEASE Kishikawa, S., Li, J., Gillis, T., Hakky, M. M., Warby, S., Hayden, M., MacDonald, M. E., Myers, R. H., Gusella, J. F. 2006; 24 (2): 280-285

    Abstract

    In Huntington's disease (HD), genetic factors in addition to the HD CAG repeat mutation play a significant role in determining age at neurologic onset. Brain-derived neurotrophic factor (BDNF), a survival factor for striatal neurons, has been implicated as a target of regulation by huntingtin and is an attractive candidate as a genetic modifier. We tested this hypothesis by genotyping a SNP known to alter BDNF function (rs6265, also termed Val66Met) and a SNP associated with Alzheimer disease (BDNF C270T), along with two BDNF intronic SNPs (rs7103411, rs11030104), in 228 cases with extreme young onset and 329 cases with extreme old onset of HD. No differences were seen between groups for allele frequencies or genotype frequencies for any SNP. Furthermore, no association to onset age was seen in GEE models controlling for HD repeat size or in haplotype analyses of these SNPs. These results indicate that BDNF does not influence significantly the mechanisms in HD pathogenesis that lead to neurologic onset.

    View details for DOI 10.1016/j.nbd.2006.07.008

    View details for Web of Science ID 000241594900007

    View details for PubMedID 16962786

  • Predictive testing for Huntington disease: interpretation and significance of intermediate alleles CLINICAL GENETICS Semaka, A., Creighton, S., Warby, S., Hayden, M. R. 2006; 70 (4): 283-294

    Abstract

    Direct mutation analysis for Huntington disease (HD) became possible in 1993 with the identification of an expanded CAG trinucleotide repeat as the mutation underlying the disease. Expansion of CAG length beyond 35 repeats may be associated with the clinical presentation of HD. HD has never been seen in a person with a CAG size of <36 repeats. Intermediate alleles are defined as being below the affected CAG range but have the potential to expand to >35 CAG repeats within one generation. Thus, children of intermediate allele carriers have a low risk of developing HD. Currently, the intermediate allele range for HD is between 27 and 35 CAG repeats. In this study, we review the current knowledge on intermediate alleles for HD including the CAG repeat range, the intermediate allele frequency, and the clinical implications of an intermediate allele predictive test result. The factors influencing CAG repeat expansion, including the CAG size of the intermediate allele, the sex and age of the transmitting parent, the family history, and the HD gene sequence and haplotype, will also be reviewed.

    View details for DOI 10.1111/j.1399-0004.2006.00668.x

    View details for Web of Science ID 000240312600003

    View details for PubMedID 16965319

  • Genome-wide significance for a modifier of age at neurological onset in Huntington's Disease at 6q23-24: the HD MAPS study BMC MEDICAL GENETICS Li, J., Hayden, M. R., Warby, S. C., Durr, A., Morrison, P. J., Nance, M., Ross, C. A., Margolis, R. L., Rosenblatt, A., Squitieri, F., Frati, L., Gomez-Tortosa, E., Garcia, C. A., Suchowersky, O., Klimek, M. L., Trent, R. J., McCusker, E., Novelletto, A., Frontali, M., Paulsen, J. S., Jones, R., Ashizawa, T., Lazzarini, A., Wheeler, V. C., Prakash, R., Xu, G., Djousse, L., Mysore, J. S., Gillis, T., Hakky, M., Cupples, A., Saint-Hilaire, M. H., Cha, J. J., Hersch, S. M., Penney, J. B., Harrison, M. B., Perlman, S. L., Zanko, A., Abramson, R. K., Lechich, A. J., Duckett, A., Marder, K., Conneally, P. M., Gusella, J. F., MacDonald, M. E., Myers, R. H. 2006; 7

    Abstract

    Age at onset of Huntington's disease (HD) is correlated with the size of the abnormal CAG repeat expansion in the HD gene; however, several studies have indicated that other genetic factors also contribute to the variability in HD age at onset. To identify modifier genes, we recently reported a whole-genome scan in a sample of 629 affected sibling pairs from 295 pedigrees, in which six genomic regions provided suggestive evidence for quantitative trait loci (QTL), modifying age at onset in HD.In order to test the replication of this finding, eighteen microsatellite markers, three from each of the six genomic regions, were genotyped in 102 newly recruited sibling pairs from 69 pedigrees, and data were analyzed, using a multipoint linkage variance component method, in the follow-up sample and the combined sample of 352 pedigrees with 753 sibling pairs.Suggestive evidence for linkage at 6q23-24 in the follow-up sample (LOD = 1.87, p = 0.002) increased to genome-wide significance for linkage in the combined sample (LOD = 4.05, p = 0.00001), while suggestive evidence for linkage was observed at 18q22, in both the follow-up sample (LOD = 0.79, p = 0.03) and the combined sample (LOD = 1.78, p = 0.002). Epistatic analysis indicated that there is no interaction between 6q23-24 and other loci.In this replication study, linkage for modifier of age at onset in HD was confirmed at 6q23-24. Evidence for linkage was also found at 18q22. The demonstration of statistically significant linkage to a potential modifier locus opens the path to location cloning of a gene capable of altering HD pathogenesis, which could provide a validated target for therapeutic development in the human patient.

    View details for DOI 10.1186/1471-2350-7-71

    View details for Web of Science ID 000240993100001

    View details for PubMedID 16914060

  • Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin CELL Graham, R. K., Deng, Y., Slow, E. J., Haigh, B., Bissada, N., Lu, G., Pearson, J., Shehadeh, J., Bertram, L., Murphy, Z., Warby, S. C., Doty, C. N., Roy, S., Wellinpton, C. L., Leavitt, B. R., Raymond, L. A., Nicholson, D. W., Hayden, M. R. 2006; 125 (6): 1179-1191

    Abstract

    Cleavage of huntingtin (htt) has been characterized in vitro, and accumulation of caspase cleavage fragments represents an early pathological change in brains of Huntington's disease (HD) patients. However, the relationship between htt proteolysis and the pathogenesis of HD is unknown. To determine whether caspase cleavage of htt is a key event in the neuronal dysfunction and selective neurodegeneration in HD, we generated YAC mice expressing caspase-3- and caspase-6-resistant mutant htt. Mice expressing mutant htt, resistant to cleavage by caspase-6 but not caspase-3, maintain normal neuronal function and do not develop striatal neurodegeneration. Furthermore, caspase-6-resistant mutant htt mice are protected against neurotoxicity induced by multiple stressors including NMDA, quinolinic acid (QA), and staurosporine. These results are consistent with proteolysis of htt at the caspase-6 cleavage site being an important event in mediating neuronal dysfunction and neurodegeneration and highlight the significant role of htt proteolysis and excitotoxicity in HD.

    View details for DOI 10.1016/j.cell.2006.04.026

    View details for Web of Science ID 000238602700021

    View details for PubMedID 16777606

  • FASA-57 cDNA shares no homology with coding sequence of HD gene JOURNAL OF REPRODUCTIVE IMMUNOLOGY Warby, S., MacDonald, M., Hayden, M., Butland, S., Ouellette, F. 2006; 69 (1): 9-10

    View details for DOI 10.1016/j.iri.2005.10.002

    View details for Web of Science ID 000235407200002

    View details for PubMedID 16386309

  • Huntingtin phosphorylation on serine 421 is significantly reduced in the striatum and by polyglutamine expansion in vivo HUMAN MOLECULAR GENETICS Warby, S. C., Chan, E. Y., Metzler, M., Gan, L., Singaraja, R. R., Crocker, S. F., Robertson, H. A., Hayden, M. R. 2005; 14 (11): 1569-1577

    Abstract

    Huntington disease (HD) results from polyglutamine expansion in the huntingtin protein (htt). Despite the widespread tissue expression pattern of htt, neuronal loss is highly selective to medium spiny neurons of the striatum. Huntingtin is phosphorylated on serine-421 (S421) by the pro-survival signaling protein kinase Akt (PKB) and this has been previously shown to be protective against the toxicity of polyglutamine-expanded htt in cell culture. Using an antibody specific for htt phosphorylated on S421, we now demonstrate that htt phosphorylation is present at significant levels under normal physiological conditions in human and mouse brain. Furthermore, htt phosphorylation shows a regional distribution with the highest levels in the cerebellum, less in the cortex, and least in the striatum. In cell cultures and in YAC transgenic mice, the endogenous phosphorylation of polyglutamine-expanded htt is significantly reduced relative to wild-type htt. The presence and pattern of significant htt phosphorylation in the brain indicates that this dynamic post-translational modification is important for the regulation of htt and may contribute to the selective neurodegeneration seen in HD.

    View details for DOI 10.1093/hmg/ddi165

    View details for Web of Science ID 000229286100016

    View details for PubMedID 15843398

  • Modeling classic female Rett Syndrome in male mice CLINICAL GENETICS Warby, S., Chopra, V., Chan, E. Y. 2002; 62 (5): 368-370

    View details for Web of Science ID 000179194400003

    View details for PubMedID 12431249

  • HIP14, a novel ankyrin domain-containing protein, links huntingtin to intracellular trafficking and endocytosis HUMAN MOLECULAR GENETICS Singaraja, R. R., Hadano, S., Metzler, M., Givan, S., Wellington, C. L., Warby, S., Yanai, A., Gutekunst, C. A., Leavitt, B. R., Yi, H., Fichter, K., Gan, L., McCutcheon, K., Chopra, V., Michel, J., Hersch, S. M., Ikeda, J. E., Hayden, M. R. 2002; 11 (23): 2815-2828

    Abstract

    Huntington disease (HD) is caused by polyglutamine [poly(Q)] expansion in the protein huntingtin (htt). Although the exact mechanism of disease progression remains to be elucidated, altered interactions of mutant htt with its protein partners could contribute to the disease. Using the yeast two-hybrid system, we have isolated a novel htt interacting protein, HIP14. HIP14's interaction with htt is inversely correlated to the poly(Q) length in htt. mRNAs of 9 and 6 bp are transcribed from the HIP14 gene, with the 6 kb transcript being predominantly expressed in the brain. HIP14 protein is enriched in the brain, shows partial co-localization with htt in the striatum, and is found in medium spiny projection neurons, the subset of neurons affected in HD. HIP14 localizes to the Golgi, and to vesicles in the cytoplasm. The HIP14 protein has sequence similarity to Akr1p, a protein essential for endocytosis in Saccharomyces cerevisiae. Expression of human HIP14 results in rescue of the temperature-sensitive lethality in akr1 Delta yeast cells and, furthermore, restores their defect in endocytosis, demonstrating a role for HIP14 in intracellular trafficking. Our findings suggest that decreased interaction between htt and HIP14 could contribute to the neuronal dysfunction in HD by perturbing normal intracellular transport pathways in neurons.

    View details for Web of Science ID 000179221500002

    View details for PubMedID 12393793

  • Caspase cleavage of mutant huntingtin precedes neurodegeneration in Huntington's disease JOURNAL OF NEUROSCIENCE Wellington, C. L., Ellerby, L. M., Gutekunst, C. A., Rogers, D., Warby, S., Graham, R. K., Loubser, O., Van Raamsdonk, J., Singaraja, R., Yang, Y. Z., Gafni, J., Bredesen, D., Hersch, S. M., Leavitt, B. R., Roy, S., Nicholson, D. W., Hayden, M. R. 2002; 22 (18): 7862-7872

    Abstract

    Huntington's disease (HD) results from polyglutamine expansion in huntingtin (htt), a protein with several consensus caspase cleavage sites. Despite the identification of htt fragments in the brain, it has not been shown conclusively that htt is cleaved by caspases in vivo. Furthermore, no study has addressed when htt cleavage occurs with respect to the onset of neurodegeneration. Using antibodies that detect only caspase-cleaved htt, we demonstrate that htt is cleaved in vivo specifically at the caspase consensus site at amino acid 552. We detect caspase-cleaved htt in control human brain as well as in HD brains with early grade neuropathology, including one homozygote. Cleaved htt is also seen in wild-type and HD transgenic mouse brains before the onset of neurodegeneration. These results suggest that caspase cleavage of htt may be a normal physiological event. However, in HD, cleavage of mutant htt would release N-terminal fragments with the potential for increased toxicity and accumulation caused by the presence of the expanded polyglutamine tract. Furthermore, htt fragments were detected most abundantly in cortical projection neurons, suggesting that accumulation of expanded htt fragments in these neurons may lead to corticostriatal dysfunction as an early event in the pathogenesis of HD.

    View details for Web of Science ID 000177916000006

    View details for PubMedID 12223539

  • Huntingtin interacting protein 1 induces apoptosis via a novel caspase-dependent death effector domain JOURNAL OF BIOLOGICAL CHEMISTRY Hackam, A. S., Yassa, A. S., Singaraja, R., Metzler, M., Gutekunst, C. A., Gan, L., Warby, S., Wellington, C. L., Vaillancourt, J., Chen, N. S., Gervais, F. G., Raymond, L., Nicholson, D. W., Hayden, M. R. 2000; 275 (52): 41299-41308

    Abstract

    Huntington disease is a devastating neurodegenerative disease caused by the expansion of a polymorphic glutamine tract in huntingtin. The huntingtin interacting protein (HIP-1) was identified by its altered interaction with mutant huntingtin. However, the function of HIP-1 was not known. In this study, we identify HIP-1 as a proapoptotic protein. Overexpression of HIP-1 resulted in rapid caspase 3-dependent cell death. Bioinformatics analyses identified a novel domain in HIP-1 with homology to death effector domains (DEDs) present in proteins involved in apoptosis. Expression of the HIP-1 DED alone resulted in cell death indistinguishable from HIP-1, indicating that the DED is responsible for HIP-1 toxicity. Furthermore, substitution of a conserved hydrophobic phenylalanine residue within the HIP-1 DED at position 398 eliminated HIP-1 toxicity entirely. HIP-1 activity was found to be independent of the DED-containing caspase 8 but was significantly inhibited by the antiapoptotic protein Bcl-x(L), implicating the intrinsic pathway of apoptosis in HIP-1-induced cell death. Co-expression of a normal huntingtin fragment capable of binding HIP-1 significantly reduced cell death. Our data identify HIP-1 as a novel proapoptotic mediator and suggest that HIP-1 may be a molecular accomplice in the pathogenesis of Huntington disease.

    View details for Web of Science ID 000166114600085

    View details for PubMedID 11007801

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