Showing papers by "Guy A. Rouleau published in 2006"
TL;DR: Five mutations in the maternal gene NALP7 in individuals with familial and recurrent HMs are reported, which is the first maternal effect gene identified in humans and is also responsible for recurrent spontaneous abortions, stillbirths and intrauterine growth retardation.
Abstract: Hydatidiform mole (HM) is an abnormal human pregnancy with no embryo and cystic degeneration of placental villi. We report five mutations in the maternal gene NALP7 in individuals with familial and recurrent HMs. NALP7 is a member of the CATERPILLER protein family involved in inflammation and apoptosis. NALP7 is the first maternal effect gene identified in humans and is also responsible for recurrent spontaneous abortions, stillbirths and intrauterine growth retardation.
412 citations
TL;DR: The pathways leading to the specific motor neurons degeneration in the presence of SOD1 mutations have not been fully identified and this review provides an overview of the genetics of both familial and sporadic forms of ALS.
244 citations
TL;DR: It appears that the covariation of depressive symptoms and CAD may be attributable, in part, to a common genetic vulnerability; genes within the inflammation and serotonin pathways may serve as good candidates for the first steps in identifying genetic variation important for depression, CAD or both.
Abstract: Objective:Although it is well established that depressive symptoms are associated with recurrent cardiac events among cardiac patients and novel cardiac events among participants with no known coronary artery disease (CAD), the nature of this association remains unclear. In this regard, little atten
183 citations
TL;DR: A role for SSAT, the rate-limiting enzyme in the catabolism of polyamines, in suicide and depression and a role for the SSAT342 locus in the regulation of SSAT gene expression are suggested.
Abstract: Context: A large body of evidence suggests that predisposition to suicide, an important public health problem, is mediated to a certain extent by neurobiological factors. Objective: To investigate patterns of expression in suicide with and without major depression and to identify new molecular targets that may play a role in the neurobiology of these conditions. Design: Brain gene expression analysis was performed using the Affymetrix HG-U133 chipset in the orbital cortex (Brodmann area [BA]11), the dorsolateral prefrontal cortex (BA8/9), and motor cortex (BA4). Subsequent studies were carried out in independent samples from adjacent areas to validate positive findings, confirm their relevance at the protein level, and investigate possible effects of genetic variation.
161 citations
TL;DR: A large fraction of the human gene repertoire remains phenotypically uncharacterized, and is likely to encode many unanticipated and novel phenotypes that will be of interest to pharmaceutical and biotechnological drug developers.
Abstract: The decrease in new drug applications and approvals over the past several years results from an underlying crisis in drug target identification and validation. Model organisms are being used to address this problem, in combination with novel approaches such as the International HapMap Project. What has been underappreciated is that discovery of new drug targets can also be revived by traditional Mendelian genetics. A large fraction of the human gene repertoire remains phenotypically uncharacterized, and is likely to encode many unanticipated and novel phenotypes that will be of interest to pharmaceutical and biotechnological drug developers.
81 citations
TL;DR: The 5-HTT gene-linked polymorphic region (5-HTTLPR) and intron 2 (STin2) variants of this gene and their relationship to behavioral and clinical risk factors for suicide are investigated to identify predictors of suicide.
57 citations
TL;DR: A group of 23 French-Canadian cases belonging to 17 families affected by an autosomal recessive spastic ataxia associated with frequent white matter changes is identified, pointing to a common pathway for pyramidal and cerebellar degeneration as both are often observed in recessive ataxias and complicated paraplegias.
Abstract: Recessive ataxias are a heterogeneous group of diseases We identified a group of 23 French–Canadian cases belonging to 17 families affected by an autosomal recessive spastic ataxia associated with frequent white matter changes The fact that 59% of these families have a genealogical relationship to the Portneuf County of Quebec suggests that this is a new form of ataxia with a regional founder effect All cases present with cerebellar ataxia and spasticity There is great intrafamilial and interfamilial variability, as illustrated by the spectrum of age of diagnosis (range: 2–59 years, mean: 150) and the presence of white matter changes on MRI in 524% of cases The more severe cases have spasticity from birth, scoliosis, dystonia and cognitive impairment and were considered cases of cerebral palsy Brain MRI constantly shows cerebellar atrophy, which in some cases may be associated with cortical atrophy, leucoencephalopathy and corpus callosum thinning A genome wide scan uncovered linkage of three families to marker D2S2321 localized on chromosome 2q33–34 Linkage analysis confirmed that all families are linked to the same region [multipoint log of the odds (LOD) score of 595] Haplotype analysis and allele sharing suggest that one common mutation may account for 97% of carrier chromosomes in Quebec The uncovering of the mutated gene may point to a common pathway for pyramidal and cerebellar degeneration as both are often observed in recessive ataxias and complicated paraplegias
50 citations
TL;DR: It is predicted that the regional populations of Canada will allow the identification of new rare forms of hereditary ataxias, spastic parapareses and neuropathies, and contribute to the unravelling of the genetic basis of these entities.
Abstract: Historical events have shaped the various regional gene pools of the French-Canadian (FC) population, leading to increased prevalence of some rare diseases. The first studies of these founder effects were performed in large part by astute clinicians such as Andre Barbeau. In collaboration with others, he contributed greatly to the delineation of phenotypic subtypes of these conditions. As such, the following neurogenetic disorders were first identified in patients of FC origin: AOA2, ARSACS, HSAN2, RAB, and HMSN/ACC. We have summarized our current knowledge of the main hereditary ataxias, spastic parapareses and neuropathies that are particular to the FC population. The initial genetic characterization of the more common and homogeneous of these diseases has been largely completed. We predict that the regional populations of Canada will allow the identification of new rare forms of hereditary ataxias, spastic parapareses and neuropathies, and contribute to the unravelling of the genetic basis of these entities.
34 citations
TL;DR: The complexity of HSR in hemodialysis is highlighted, suggesting, as with angioedema, that these rare, but life-threatening adverse events are governed by several metabolic and genetic factors.
28 citations
TL;DR: Results provide support for the existence of a locus on the X chromosome that predisposes males from French-Canadian origin to autism spectrum disorders.
Abstract: It is now well established that genetic factors play an important role in the pathogenesis of autism disorder and converging lines of evidence suggest the implication of the X chromosome. Using a sample of subjects diagnosed with autism spectrum disorders, exclusively composed of males from French-Canadian (FC) origin, we tested markers covering the entire X chromosome using a family-based association study. Our initial analysis revealed the presence of association at two loci: DXS6789 (P=0.026) and DXS8043 (P=0.0101). In a second step, we added support to the association at DXS8043 using additional markers, additional subjects and a haplotype-based analysis (best obtained P-value=0.00001). These results provide support for the existence of a locus on the X chromosome that predisposes the FC to autism spectrum disorders.
21 citations
TL;DR: The observations demonstrated that the GFP-b13AlaPABPN1 INIs are dynamic structures that can disassemble during mitosis, however, their presence in cells occasionally led to apoptosis, which could contribute in vivo to the late onset of this disease.
TL;DR: Results from the family-based and case-control association study suggest that there is no association between the trinucleotide repeat polymorphism within SMARCA2 and schizophrenia.
Abstract: Brahma (BRM) is a key component of the multisubunit SWI/SNF complex, a complex which uses the energy of ATP hydrolysis to remodel chromatin. BRM contains an N-terminal polyglutamine domain, encoded by a polymorphic trinucleotide (CAA/CAG) repeat, the only known polymorphism in the coding region of the gene (SMARCA2). We have examined the association of this polymorphism with schizophrenia in a family-based and case/control study. SMARCA2 was chosen as a candidate gene because of its specific role in developmental pathways, its high expression level in the brain and some evidence of its association with schizophrenia spectrum disorder from genome-wide linkage analysis. Family-based analysis with 281 complete and incomplete triads showed that there is no significant preferential transmission of any of the alleles to the affected offspring. Also, in the case/control analysis, similar allele and genotype distributions were observed between affected cases (n = 289) and unaffected controls (n = 273) in each of three Caucasian populations studied: French Canadian, Tunisian and other Caucasians of European origin. Results from our family-based and case-control association study suggest that there is no association between the trinucleotide repeat polymorphism within SMARCA2 and schizophrenia.
TL;DR: In HMSN-ACC patients with KCC3 mutants, RBC KCC activity, although indistinguishable from that of the control group, responded differently to biochemical stressors, such as thiol alkylation or Mg removal, thereby indirectly indicating an important contribution of K CC3 to overall KCC function and regulation.
Abstract: Red blood cells (RBCs) possess the K–Cl cotransport (KCC) isoforms 1, 3, and 4. Mutations within a given isoform may affect overall KCC activity. In a double-blind study, we analyzed, with Rb as a ...
TL;DR: Using recombinant congenic strains of mice derived from A/J and C57BL/6J to identify potential quantitative trait loci associated with AMPH-TDIST may help to identify suitable candidate genes relevant to human disorders where mesolimbic dopamine dysregulation has been postulated.
Abstract: Amphetamine (AMPH)-induced locomotor activity is a rodent behavioral trait that reflects mesolimbic dopaminergic activity. To identify potential quantitative trait loci (QTL) associated with this behavior, we used 34 recombinant congenic strains (RCSs) of mice derived from A/J (A strains) and C57BL/6J (B strains) and measured AMPH-induced total distance traveled (AMPH-TDIST). Two strains in the A panel (A52 and A63) showed significantly elevated AMPH-TDIST compared to the parental A/J strain and behaved similarly to C57BL/6J. Simple sequence length polymorphism (SSLP) markers on chromosomes 1, 2, 3, 5, 6, 8, 9, 10 and 20 were significantly associated with AMPH-TDIST in the A strains. Within the B panel, two strains (B81 and B74) had significantly higher and two strains (B69 and B75) had significantly lower AMPH-TDIST than C57BL/6J. Markers associated with AMPH-TDIST in the B strains appeared on chromosomes 5, 17 and 20. Combining data from this approach and other genetic (mapping data in humans) and functional (cDNA expression) sources may help to identify suitable candidate genes relevant to human disorders where mesolimbic dopamine dysregulation has been postulated.
TL;DR: Evidence is provided for the presence of NF2 protein in the human erythrocyte membrane that is distinct from the known membrane interactions of protein 4.1, which is an autosomal dominant disease predisposing individuals to the risk of developing tumors of cranial and spinal nerves.
Abstract: Purification de la proteine codee par le gene suppresseur de tumeur NF2 a partir d'erythrocytes humains. Contexte: La neurofibromatose de type 2 (NF2) est une maladie dominante autosomique qui predispose au developpement de tumeurs au niveau des nerfs crâniens et des nerfs spinaux. La proteine codee par le gene suppresseur de tumeurs NF2, connue sous le nom de Merlin/Schwannomin, fait partie de la superfamille des proteines 4,1 impliquees dans l'interface entre le cytosquelette et la membrane plasmatique. Methodes: Lors de l'extraction selective des proteines associees a la membrane cellulaire d'erythrocytes plasmatiques (fantomes d'hematies) au moyen d'une solution dont la force ionique est faible, la majeure partie de la proteine NF2 demeure associee aux vesicules inversees depourvues de spectrine-actine. L'analyse par buvardage Western a demontre la presence d'un polypeptide de ∼70 kDa dans la membrane plasmatique erythrocytaire. L'elimination quantitative de la proteine NF2 des vesicules inversees a ete effectuee au moyen d'iodure de potassium 1,0 M, un traitement qui extrait les proteines membranaires peripheriques fortement liees. Resultats: Ces resultats sont compatibles avec un nouveau mode d'association de la proteine NF2 a la membrane erythrocytaire qui est distinct des interactions membranaires connues au sujet des proteines 4,1. Plusieurs strategies de purification fondees sur ces proprietes biochimiques ont ete elaborees pour isoler la proteine NF2 native des fantomes d'hematies humaines. Nous avons quantifie approximativement ∼41-65 000 molecules de proteine NF2 par erythrocyte en utilisant la proteine NF2 purifiee et la proteine NF2 recombinante comme standards internes. Conclusion: Ces donnees sont compatibles avec la presence de la proteine NF2 dans la membrane des erythrocytes humains. L'identification de la proteine NF2 dans la membrane des erythrocytes humains permettra de decouvrir de nouveaux modes d'interactions de la proteine NF2 dans les cellules de mammiferes au moyen de techniques puissantes de biochimie et de genetique erythrocytaire.
Journal Article•
01 Jan 2006
TL;DR: This chapter focuses on polyalanine (polyQ) and polyglutamine (polyAla) diseases and their possible common mechanisms, which are hypothesized to progress via common cellular mechanisms.
Abstract: This chapter focuses on polyalanine (polyQ) and polyglutamine (polyAla) diseases and their possible common mechanisms. PolyQ diseases that are caused by (CAG) n repeat expansions represent the largest group of trinucleotide repeat diseases. PolyQ diseases include Huntington's disease (HD), spinobulbar muscular dystrophy (SBMA), spinocerebellar ataxia (SCA) types 1-3,6, and 7, and dentatorubral pallidoluysian atrophy. With the exception of SBMA, these neurodegenerative disorders are dominantly inherited. They all typically begin in adulthood with degeneration causing progressive neuronal dysfunction and eventually neuronal loss 10–20 years after onset of symptoms. The polyQ diseases are hypothesized to progress via common cellular mechanisms. In contrast to polyQ diseases, which cause late onset neurodegenerative diseases, all polyAla disorders, except for oculopharyngeal muscular dystrophy (OPMD) result in early developmental defects, such as malformations of the brain, digits, and other structures. All of the affected genes in polyAla diseases, except polyA binding protein 1 (PABPNl), code for in early development.