Huntington disease (HD) is an adult-onset neurodegenerative disorder that is caused by a trinucleotide CAG repeat expansion in the HTT gene that codes for the protein huntingtin (HTT in humans or Htt in mice). HTT is a multi-functional, ubiquitously expressed protein that is essential for embryonic survival, normal neurodevelopment, and adult brain function. The ability of wild-type HTT to protect neurons against various forms of death raises the possibility that loss of normal HTT function may worsen disease progression in HD. Huntingtin-lowering therapeutics are being evaluated in clinical trials for HD, but concerns have been raised that decreasing wild-type HTT levels may have adverse effects. Here we show that Htt levels modulate the occurrence of an idiopathic seizure disorder that spontaneously occurs in approximately 28% of FVB/N mice, which we have called FVB/N Seizure Disorder with SUDEP (FSDS). These abnormal FVB/N mice demonstrate the cardinal features of mouse models of epilepsy including spontaneous seizures, astrocytosis, neuronal hypertrophy, upregulation of brain-derived neurotrophic factor (BDNF), and sudden seizure-related death. Interestingly, mice heterozygous for the targeted inactivation of Htt (Htt+/- mice) exhibit an increased frequency of this disorder (71% FSDS phenotype), while over-expression of either full length wild-type HTT in YAC18 mice or full length mutant HTT in YAC128 mice completely prevents it (0% FSDS phenotype). Examination of the mechanism underlying huntingtin's ability to modulate the frequency of this seizure disorder indicated that overexpression of full length HTT can promote neuronal survival following seizures. Overall, our results demonstrate a protective role for huntingtin in this form of epilepsy and provide a plausible explanation for the observation of seizures in the juvenile form of HD, Lopes-Maciel-Rodan syndrome, and Wolf-Hirschhorn syndrome. Adverse effects caused by decreasing huntingtin levels have ramifications for huntingtin-lowering therapies that are being developed to treat HD.

Huntington disease (HD) is an adult-onset neurodegenerative disorder that is caused by a trinucleotide CAG repeat expansion in the HTT gene that codes for the protein huntingtin (HTT or Htt in mice). HTT is a multi-functional, ubiquitously expressed protein that is essential for embryonic survival, normal neurodevelopment, and adult brain function. The ability of wild-type HTT to protect neurons against various forms of death raises the possibility that loss of normal HTT function may worsen disease progression in HD. Huntingtin-lowering therapeutics are being evaluated in clinical trials for HD, but concerns have been raised that decreasing wild-type HTT levels may have adverse effects. Here we show that Htt levels modulate the occurrence of an idiopathic seizure disorder that spontaneously occurs in FVB/N mice. These abnormal FVB/N mice demonstrate various cardinal features of mouse models of epilepsy including spontaneous seizures, astrocytosis, neuronal hypertrophy, upregulation of brain-derived neurotrophic factor (BDNF), and sudden seizure-related death. Interestingly, decreasing wild-type Htt levels increased the frequency of this disorder, while over-expression of HTT completely prevented it. Examination of the mechanism underlying huntingtin’s ability to modulate the frequency of this seizure disorder indicated that over-expression of full length HTT can promote neuronal survival following seizures. Overall, our results demonstrate a protective role for huntingtin in this form of epilepsy and provide a plausible explanation for the observation of seizures in the juvenile form of HD, Lopes-Maciel-Rodan syndrome, and Wolf-Hirschhorn syndrome. Adverse effects caused by altering huntingtin levels has ramifications related to Huntingtin-lowering therapies in development to treat HD.

Defects in the human ALS2 gene, which encodes the 1,657-amino-acid residue protein alsin, are linked to several related motor neuron diseases. We created a structural model for the N-terminal 690-residue region of alsin through comparative modelling based on regulator of chromosome condensation 1 (RCC1). We propose that this alsin region contains seven RCC1-like repeats in a seven-bladed beta-propeller structure. The propeller is formed by a double clasp arrangement containing two segments (residues 1–218 and residues 525–690). The 306-residue insert region, predicted to lie within blade 5 and to be largely disordered, is poorly conserved across species. Surface patches of evolutionary conservation probably indicate locations of binding sites. Both disease-causing missense mutations—Cys157Tyr and Gly540Glu—are buried in the propeller and likely to be structurally disruptive. This study aids design of experimental studies by highlighting the importance of construct length, will enhance interpretation of protein–protein interactions, and enable rational site-directed mutagenesis.

Background: Expansion of polyglutamine-encoding CAG trinucleotide repeats has been identified as the pathogenic mutation in nine different genes associated with neurodegenerative disorders. The majority of individuals clinically diagnosed with spinocerebellar ataxia do not have mutations within known disease genes, and it is likely that additional ataxias or Huntington disease-like disorders will be found to be caused by this common mutational mechanism. We set out to determine the length distributions of CAG-polyglutamine tracts for the entire human genome in a set of healthy individuals in order to characterize the nature of polyglutamine repeat length variation across the human genome, to establish the background against which pathogenic repeat expansions can be detected, and to prioritize candidate genes for repeat expansion disorders.Results: We found that repeats, including those in known disease genes, have unique distributions of glutamine tract lengths, as measured by fragment analysis of PCR-amplified repeat regions. This emphasizes the need to characterize each distribution and avoid making generalizations between loci. The best predictors of known disease genes were occurrence of a long CAG-tract uninterrupted by CAA codons in their reference genome sequence, and high glutamine tract length variance in the normal population. We used these parameters to identify eight priority candidate genes for polyglutamine expansion disorders. Twelve CAG-polyglutamine repeats were invariant and these can likely be excluded as candidates. We outline some confusion in the literature about this type of data, difficulties in comparing such data between publications, and its application to studies of disease prevalence in different populations. Analysis of Gene Ontology-based functions of CAG-polyglutamine-containing genes provided a visual framework for interpretation of these genes' functions. All nine known disease genes were involved in DNA-dependent regulation of transcription or in neurogenesis, as were all of the well-characterized priority candidate genes.Conclusion: This publication makes freely available the normal distributions of CAG-polyglutamine repeats in the human genome. Using these background distributions, against which pathogenic expansions can be identified, we have begun screening for mutations in individuals clinically diagnosed with novel forms of spinocerebellar ataxia or Huntington disease-like disorders who do not have identified mutations within the known disease-associated genes.

Several forms of genetically defined juvenile amy-otrophic lateral sclerosis (ALS) have now been charac-terized and discussion of these conditions will form the basis for this chapter. ALS2 is an autosomal recessive form of ALS with a juvenile onset and very slow progression that mapped to chromosome 2q33. Nine different mutations have been identified in the ALS2 gene that result in premature stop codons, suggesting a loss of function in the gene product, alsin. The alsin protein is thought to function as a guanine-nucleotide exchange factor for GTPases and may play a role in vesicle transport or membrane trafficking processes. ALS4 is an autosomal dominant form of juvenile onset ALS associated with slow progression, severe muscle weakness and pyramidal signs, in the absence of bulbar and sensory abnormalities. Mutations in the SETX gene cause ALS4, and the SETX gene product senataxin may have DNA and RNA helicase activity and play a role in the regulation of RNA and/or DNA in the cell. A third form of juvenile-onset ALS (ALS5) is associated with slowly progressing lower motor neuron signs (weak-ness and atrophy) initially of the hands and feet, with eventual bulbar involvement. Progressive upper motor neuron disease becomes more obvious with time. ALS5 has been linked to a 6 cM region of chromosome 15q15.1-q21.1, but the causative gene mutation for ALS5 has yet to be identified. The high degree of clin-ical and genetic heterogeneity in the various forms of juvenile ALS can make differential diagnosis difficult, other genetic disorders that must be considered include: spinal muscular atrophy, hereditary spastic paraplegia, SBMA, GM2 gangliosidosis and the hereditary motor neuronopathies/motor forms of Charcot-Marie-Tooth disease. Acquired disorders that must also be consid-ered include heavy metal intoxications (especially lead), multifocal motor neuropathy, paraneoplastic syndromes, vitamin deficiencies (B12) and infections (HTLV-II, HIV and poliomyelitis).

2006;177;8202-8211 J. Immunol. David P. Speert Turvey, Robert E. W. Hancock, Rebecca S. Devon and Puel, Capucine Picard, Jean-Laurent Casanova, Stuart E. Rebecca C. Ma, Johan Bylund, Paul A. Campsall, Anne Bowdish, Kelly L. Brown, Carrie M. Rosenberger, Donald J. Davidson, Andrew J. Currie, Dawn M. E. Myeloid and Non-Myeloid Cells TLR/IL-1R Responses in Human Defective Post-Transcriptional Detection and Characterization of Mutation (Q293X): Rapid IRAK-4

Innate immunodeficiency has recently been reported as resulting from the Q293X IRAK-4 mutation with consequent defective TLR/IL-1R signaling. In this study we report a method for the rapid allele-specific detection of this mutation and demonstrate both cell type specificity and ligand specificity in defective IL-1R-associated kinase (IRAK) 4-deficient cellular responses, indicating differential roles for this protein in human PBMCs and primary dermal fibroblasts and in LPS, IL-1 beta, and TNF-alpha signaling. We demonstrate transcriptional and post-transcriptional defects despite NF-kappa B signaling and intact MyD88-independent signaling and propose that dysfunctional complex 1 (IRAK1/TRAF6/TAK1) signaling, as a consequence of IRAK-4 deficiency, generates specific defects in MAPK activation that could underpin this patient's innate immunodeficiency. These studies demonstrate the importance of studying primary human cells bearing a clinically relevant mutation; they underscore the complexity of innate immune signaling and illuminate novel roles for IRAK-4 and the fundamental importance of accessory proinflammatory signaling to normal human innate immune responses and, inummodeficiencies.

BACKGROUND:Many cases of frontotemporal dementia (FTD) are familial, often with an autosomal dominant pattern of inheritance. Some are due to a mutation in the tau- encoding gene, on chromosome 17, and show an accumulation of abnormal tau in brain tissue (FTDP-17T). Most of the remaining familial cases do not exhibit tau pathology, but display neuropathology similar to patients with dementia and motor neuron disease, characterized by the presence of ubiquitin-immunoreactive (ub-ir), dystrophic neurites and neuronal cytoplasmic inclusions in the neocortex and hippocampus (FTLD-U). Recently, we described a subset of patients with familial FTD with autopsy-proven FTLD-U pathology and with the additional finding of ub-ir neuronal intranuclear inclusions (NII). NII are a characteristic feature of several other neurodegenerative conditions for which the genetic basis is abnormal expansion of a polyglutamine-encoding trinucleotide repeat region. The genetic basis of familial FTLD-U is currently not known, however the presence of NII suggests that a subset of cases may represent a polyglutamine expansion disease.METHODS:We studied DNA and post mortem brain tissue from 5 affected members of 4 different families with NII and one affected individual with familial FTLD-U without NII. Patient DNA was screened for CAA/CAG trinucleotide expansion in a set of candidate genes identified using a genome-wide computational approach. Genes containing CAA/CAG trinucleotide repeats encoding at least five glutamines were examined (n = 63), including the nine genes currently known to be associated with human disease. CAA/CAG tract sizes were compared with published normal values (where available) and with those of healthy controls (n = 94). High-resolution agarose gel electrophoresis was used to measure allele size (number of CAA/CAG repeats). For any alleles estimated to be equal to or larger than the maximum measured in the control population, the CAA/CAG tract length was confirmed by capillary electrophoresis. In addition, immunohistochemistry using a monoclonal antibody that recognizes proteins containing expanded polyglutamines (1C2) was performed on sections of post mortem brain tissue from subjects with NII.RESULTS:No significant polyglutamine-encoding repeat expansions were identified in the DNA from any of our FTLD-U patients. NII in the FTLD-U cases showed no 1C2 immunoreactivity.CONCLUSION:We find no evidence to suggest that autosomal dominant FTLD-U with NII is a polyglutamine expansion disease.

Background To date, 35 human diseases, some of which also exhibit anticipation, have been associated with unstable repeats. Anticipation has been reported in a number of diseases in which repeat expansion may have a role in etiology. Despite the growing importance of unstable repeats in disease, currently no resource exists for the prioritization of repeats. Here we present Satellog, a database that catalogs all pure 1–16 repeat unit satellite repeats in the human genome along with supplementary data. Satellog analyzes each pure repeat in UniGene clusters for evidence of repeat polymorphism. Results A total of 5,546 such repeats were identified, providing the first indication of many novel polymorphic sites in the genome. Overall, polymorphic repeats were over-represented within 3'-UTR sequence relative to 5'-UTR and coding sequence. Interestingly, we observed that repeat polymorphism within coding sequence is restricted to trinucleotide repeats whereas UTR sequence tolerated a wider range of repeat period polymorphisms. For each pure repeat we also calculate its repeat length percentile rank, its location either within or adjacent to EnsEMBL genes, and its expression profile in normal tissues according to the GeneNote database. Conclusion Satellog provides the ability to dynamically prioritize repeats based on any of their characteristics (i.e. repeat unit, class, period, length, repeat length percentile rank, genomic co-ordinates), polymorphism profile within UniGene, proximity to or presence within gene regions (i.e. cds, UTR, 15 kb upstream etc.), metadata of the genes they are detected within and gene expression profiles within normal human tissues. Unstable repeats associated with 31 diseases were analyzed in Satellog to evaluate their common repeat properties. The utility of Satellog was highlighted by prioritizing repeats for Huntington's disease and schizophrenia. Satellog is available online at http://satellog.bcgsc.ca .

Annals of NeurologyVolume 53, Issue 1 p. 144-145 Letters An ALS2 gene mutation causes hereditary spastic paraplegia in a Pakistani kindred François Gros-Louis MSc, François Gros-Louis MSc McGill University Health Centre Research Institute and Centre for Research in Neuroscience, Montreal, QuebecSearch for more papers by this authorInge A. Meijer BSc, Inge A. Meijer BSc McGill University Health Centre Research Institute and Centre for Research in Neuroscience, Montreal, QuebecSearch for more papers by this authorCollette K. Hand PhD, Collette K. Hand PhD McGill University Health Centre Research Institute and Centre for Research in Neuroscience, Montreal, QuebecSearch for more papers by this authorMarie-Pierre Dubé PhD, Marie-Pierre Dubé PhD McGill University Health Centre Research Institute and Centre for Research in Neuroscience, Montreal, QuebecSearch for more papers by this authorDaune L. MacGregor MD, Daune L. MacGregor MD Hospital for Sick Children and University of Toronto, Toronto, ONSearch for more papers by this authorMarie-Hélène Seni RT, Marie-Hélène Seni RT Neurogenetics Unit, Montreal Neurological Hospital and Institute, McGill University, Montreal, QuebecSearch for more papers by this authorRebecca S. Devon PhD, Rebecca S. Devon PhD Centre for Molecular Medicine and Therapeutics, Vancouver, British ColumbiaSearch for more papers by this authorMichael R. Hayden MD, PhD, Michael R. Hayden MD, PhD Centre for Molecular Medicine and Therapeutics, Vancouver, British ColumbiaSearch for more papers by this authorFrederick Andermann MD, Frederick Andermann MD Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada Department of Pediatrics, and , McGill University, Montreal, Quebec, CanadaSearch for more papers by this authorEva Andermann MD, PhD, Eva Andermann MD, PhD Neurogenetics Unit, Montreal Neurological Hospital and Institute, McGill University, Montreal, Quebec Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada Department of Human Genetics, McGill University, Montreal, Quebec, CanadaSearch for more papers by this authorGuy A. Rouleau MD, PhD, Guy A. Rouleau MD, PhD McGill University Health Centre Research Institute and Centre for Research in Neuroscience, Montreal, QuebecSearch for more papers by this author François Gros-Louis MSc, François Gros-Louis MSc McGill University Health Centre Research Institute and Centre for Research in Neuroscience, Montreal, QuebecSearch for more papers by this authorInge A. Meijer BSc, Inge A. Meijer BSc McGill University Health Centre Research Institute and Centre for Research in Neuroscience, Montreal, QuebecSearch for more papers by this authorCollette K. Hand PhD, Collette K. Hand PhD McGill University Health Centre Research Institute and Centre for Research in Neuroscience, Montreal, QuebecSearch for more papers by this authorMarie-Pierre Dubé PhD, Marie-Pierre Dubé PhD McGill University Health Centre Research Institute and Centre for Research in Neuroscience, Montreal, QuebecSearch for more papers by this authorDaune L. MacGregor MD, Daune L. MacGregor MD Hospital for Sick Children and University of Toronto, Toronto, ONSearch for more papers by this authorMarie-Hélène Seni RT, Marie-Hélène Seni RT Neurogenetics Unit, Montreal Neurological Hospital and Institute, McGill University, Montreal, QuebecSearch for more papers by this authorRebecca S. Devon PhD, Rebecca S. Devon PhD Centre for Molecular Medicine and Therapeutics, Vancouver, British ColumbiaSearch for more papers by this authorMichael R. Hayden MD, PhD, Michael R. Hayden MD, PhD Centre for Molecular Medicine and Therapeutics, Vancouver, British ColumbiaSearch for more papers by this authorFrederick Andermann MD, Frederick Andermann MD Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada Department of Pediatrics, and , McGill University, Montreal, Quebec, CanadaSearch for more papers by this authorEva Andermann MD, PhD, Eva Andermann MD, PhD Neurogenetics Unit, Montreal Neurological Hospital and Institute, McGill University, Montreal, Quebec Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada Department of Human Genetics, McGill University, Montreal, Quebec, CanadaSearch for more papers by this authorGuy A. Rouleau MD, PhD, Guy A. Rouleau MD, PhD McGill University Health Centre Research Institute and Centre for Research in Neuroscience, Montreal, QuebecSearch for more papers by this author First published: 31 December 2002 https://doi.org/10.1002/ana.10422Citations: 83Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. References 1 Hadano S, Hand CK, Osuga H, et al. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat Genet 2001; 29: 166– 173. 2 Yang Y, Hentati A, Deng HX, et al. The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat Genet 2001; 29: 160– 165. 3 Eymard-Pierre E, Lesca G, Dollet S, et al. Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene. Am J Hum Genet 2002; 71: 518– 527. 4 Fontaine B, Davoine CS, Durr A, et al. A new locus for autosomal dominant pure spastic paraplegia, on chromosome 2q24–q34. Am J Hum Genet 2000; 66: 702– 707. 5 Esters H, Alexandrov K, Iakovenko A, et al. Vps9, Rabex-5 and DSS4: proteins with weak but distinct nucleotide-exchange activities for Rab proteins. J Mol Biol 2001; 310: 141– 156. Citing Literature Volume53, Issue1January 2003Pages 144-145 ReferencesRelatedInformation

Huntingtin interacting protein 1 (HIP1) is a recently identified component of clathrin‐coated vesicles that plays a role in clathrin‐mediated endocytosis. To explore the normal function of HIP1 in vivo, we created mice with targeted mutation in the HIP1 gene (HIP1−/−). HIP1−/− mice develop a neurological phenotype by 3 months of age manifest with a failure to thrive, tremor and a gait ataxia secondary to a rigid thoracolumbar kyphosis accompanied by decreased assembly of endocytic protein complexes on liposomal membranes. In primary hippocampal neurons, HIP1 colocalizes with GluR1‐containing AMPA receptors and becomes concentrated in cell bodies following AMPA stimulation. Moreover, a profound dose‐dependent defect in clathrin‐mediated internalization of GluR1‐containing AMPA receptors was observed in neurons from HIP1−/− mice. Together, these data provide strong evidence that HIP1 regulates AMPA receptor trafficking in the central nervous system through its function in clathrin‐mediated endocytosis.

Amyotrophic lateral sclerosis 2 (ALS2) is an autosomal recessive form of juvenile ALS and has been mapped to human chromosome 2q33. Here we report the identification of two independent deletion mutations linked to ALS2 in the coding exons of the new gene ALS2. These deletion mutations result in frameshifts that generate premature stop codons. ALS2 is expressed in various tissues and cells, including neurons throughout the brain and spinal cord, and encodes a protein containing multiple domains that have homology to RanGEF as well as RhoGEF. Deletion mutations are predicted to cause a loss of protein function, providing strong evidence that ALS2 is the causative gene underlying this form of ALS.

The term ''coincidence cloning'' encompasses a wide range of methodologies, the aim of which is to isolate DNA sequences which occur in both of two input DNA sources. The nature of these input DNAs may be genomic or cDNA, cloned or uncloned, and as such the far reaching applicability of the techniques can be imagined. If the input DNAs are genomic then the product will be enriched for useful markers co-occurring between the two. If the input DNAs comprise one genomic resource and one cDNA resource the product will contain genes mapping to that particular genomic region. In this review a comparative description of the range of coincidence cloning methods is given, together with a discussion of their applications. Finally, consideration is given to the general limitations of these techniques.