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Guy A. Rouleau

Bio: Guy A. Rouleau is an academic researcher from Montreal Neurological Institute and Hospital. The author has contributed to research in topics: Genome-wide association study & Amyotrophic lateral sclerosis. The author has an hindex of 129, co-authored 884 publications receiving 65892 citations. Previous affiliations of Guy A. Rouleau include Utrecht University & University of Helsinki.


Papers
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Journal ArticleDOI
TL;DR: It is suggested that more effort and resources should be placed in this arena of human genetics, to complement the current enthusiasm for whole-genome SNP-association testing, and that the potential value of such genetics for new drug target validation should always be considered.
Abstract: Ségalat makes several interesting points regarding the relevance of monogenic disorders in the identification and validation of novel drug targets. Nonetheless, we feel that the comments are overly conservative. It is not the logic of our argument that is criticized by Ségalat; it is rather the practical applicability of our approach to drug and target discovery. Our approach is not exclusive, and we did not intend to imply that it would be applicable to all disease states. Our point is simply that monogenic disorders can be of value in understanding the underlying pathophysiology of many common diseases, and if so they should not be overlooked. Multiple examples of major drug programmes that are already in progress that stem from, or are influenced by, human monogenic molecular results, support our conclusion. We have suggested that more effort and resources should be placed in this arena of human genetics, to complement the current enthusiasm for whole-genome SNP-association testing, and that the potential value of such genetics for new drug target validation should always be considered. We have also noted in our article that the distinction between ‘monogenic’ and ‘complex genetics’ is more operational than theoretical, but feel that this is still a useful distinction as long as the limitations of this dichotomization are respected. Ségalat notes that the physiology of the ascertained monogenic disorders (whether molecularly characterized or not) has typically been evaluated already with respect to important common diseases. This is not in dispute. But, as we note, these represent only a fraction of all possible monogenic phenotypes, and are probably biased towards rare, not common, medical phenotypes. The null or loss-of-function allelic consequences in most human genes remain totally uncharacterized. For example, disregarding the olfactory receptors, there are approximately 370 G-protein coupled receptor (GPCR)-encoding genes, of which fewer than 40 have a defined monogenic phenotype. GPCRs are favourites of the pharmaceutical industry, and can sometimes be both agonized and antagonized by different chemistries. It is feasible that null alleles of uncharacterized GPCRs could lead to migraine, bipolar disorder, hypertension (or hypotension), obesity (or leanness) and so on. Clearly, highly penetrant dominant genetic disorders that mimic common medical conditions are not abundant, but recessive monogenic disorders that mimic common medical conditions are not easily ascertained by traditional medical genetics. Mutations in the leptin and leptin receptor genes are known in humans, but were only discovered by candidate-gene sequencing after these genes were implicated in obesity by mouse genetics. In fact, Ahituv et al.1 and Cohen et al.2 suggest that individually rare mutations in multiple genes could be additively important for understanding the total genetic burden of obesity and dyslipidemia. Ségalat notes that, “...another major problem with genetic diseases is that they have no treatment.” Although treatment remains elusive for many (but not all) genetic disease, our premise focused instead on the relevance of monogenic disorders to the treatment of a common disorders with similar physiology. We do not mean to imply that a mode of treatment can be suggested for the actual patients who suffer from the monogenic disorder: there might be in some cases, but that is not the point. Human genetics is being used as an analytical paradigm to dissect common disease pathways and to identify targetable steps. Gene therapy is a completely different issue: important, but unrelated to our logic. We do not disagree with the comment that some important medical conditions might fail to yield to single-target-based therapeutics, and that some diseases are too complex for standard pharmaceutical treatment. Some approved, psychiatrically active drugs are already known to target multiple receptor types in the brain, which might be necessary for their action. However, the human genetics community is only beginning to analyse multi-locus phenotypes, and is still at the phase in which discovering a single locus that is relevant to a common disease phenotype is a major logistical and theoretical endeavor. Moreover, it is disingenuous to assume that the pharmaceutical industry will readily adapt to a multi-target or combined-therapy paradigm for all important indications, as these add major burdens of complexity and cost to compound development. The heavy onus placed on new pharmaceutical programmes to document mechanism of action, safety and efficacy, lead de facto to reductionist approaches, even when it is clear that multiple physiological pathways

3 citations

Journal ArticleDOI
TL;DR: Results suggest that SYNE1 ataxia patients may represent a model to investigate effects of cerebellar degeneration in higher hierarchical cognitive functions, and abstract thinking impairment in schizophrenia may be related to dysfunction in cerebellum pathways.
Abstract: SYNE1 gene mutations were identified as a cause of late-onset pure cerebellar syndrome. Non-cerebellar symptoms, including cognitive impairment, were already described in this condition. The aim of this study was to perform a detailed cognitive and psychiatric description of patients with SYNE1 gene mutations. We performed neuropsychological and psychiatric evaluations of six patients with SYNE1 ataxia and compared their performance with 18 normal controls paired for age and education level. SYNE1 ataxia patients present cognitive dysfunction, characterized by impairment in attention and processing speed domains. Otherwise, the psychiatric assessment reported low levels of overall behavioral symptoms with only some minor anxiety-related complaints. Although this is a small sample of patients, these results suggest that SYNE1 ataxia patients may represent a model to investigate effects of cerebellar degeneration in higher hierarchical cognitive functions. For further studies, abstract thinking impairment in schizophrenia may be related to dysfunction in cerebellum pathways.

3 citations

Book ChapterDOI
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.

3 citations

Journal ArticleDOI
TL;DR: La neuropathie sensitivo-motrice héréditaire avec agénésie du corps calleux / Severe neuropathy with agenesis of the corpus callosum
Abstract: Montréal. Il a pour mission la promotion et la valorisation de la recherche. Érudit offre des services d'édition numérique de documents scientifiques depuis 1998. Pour communiquer avec les responsables d'Érudit : info@erudit.org Article « La neuropathie sensitivo-motrice héréditaire avec agénésie du corps calleux / Severe neuropathy with agenesis of the corpus callosum » Note : les règles d'écriture des références bibliographiques peuvent varier selon les différents domaines du savoir. Ce document est protégé par la loi sur le droit d'auteur. L'utilisation des services d'Érudit (y compris la reproduction) est assujettie à sa politique d'utilisation que vous pouvez consulter à l'URI

3 citations


Cited by
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28 Jul 2005
TL;DR: PfPMP1)与感染红细胞、树突状组胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作�ly.
Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1(PfPMP1)与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员,通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

18,940 citations

Journal ArticleDOI
01 Jun 1990-Cell
TL;DR: A model for the genetic basis of colorectal neoplasia that includes the following salient features is presented, which may be applicable to other common epithelial neoplasms, in which tumors of varying stage are more difficult to study.

11,576 citations

Journal ArticleDOI
TL;DR: A unified analytic framework to discover and genotype variation among multiple samples simultaneously that achieves sensitive and specific results across five sequencing technologies and three distinct, canonical experimental designs is presented.
Abstract: Recent advances in sequencing technology make it possible to comprehensively catalogue genetic variation in population samples, creating a foundation for understanding human disease, ancestry and evolution. The amounts of raw data produced are prodigious and many computational steps are required to translate this output into high-quality variant calls. We present a unified analytic framework to discover and genotype variation among multiple samples simultaneously that achieves sensitive and specific results across five sequencing technologies and three distinct, canonical experimental designs. Our process includes (1) initial read mapping; (2) local realignment around indels; (3) base quality score recalibration; (4) SNP discovery and genotyping to find all potential variants; and (5) machine learning to separate true segregating variation from machine artifacts common to next-generation sequencing technologies. We discuss the application of these tools, instantiated in the Genome Analysis Toolkit (GATK), to deep whole-genome, whole-exome capture, and multi-sample low-pass (~4×) 1000 Genomes Project datasets.

10,056 citations

Journal ArticleDOI
04 Mar 1993-Nature
TL;DR: Tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O–2 to O2 and H2O2 is reported.
Abstract: Amyotrophic lateral sclerosis (ALS) is a degenerative disorder of motor neurons in the cortex, brainstem and spinal cord. Its cause is unknown and it is uniformly fatal, typically within five years. About 10% of cases are inherited as an autosomal dominant trait, with high penetrance after the sixth decade. In most instances, sporadic and autosomal dominant familial ALS (FALS) are clinically similar. We have previously shown that in some but not all FALS pedigrees the disease is linked to a genetic defect on chromosome 21q (refs 8, 9). Here we report tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O2.- to O2 and H2O2 (ref. 10). Given this linkage and the potential role of free radical toxicity in other neurodenegerative disorders, we investigated SOD1 as a candidate gene in FALS. We identified 11 different SOD1 missense mutations in 13 different FALS families.

6,733 citations

Journal ArticleDOI
TL;DR: It is found that ras-gene mutations occurred in 58 percent of adenomas larger than 1 cm and in 47 percent of carcinomas, which are consistent with a model of colorectal tumorigenesis in which the steps required for the development of cancer often involve the mutational activation of an oncogene coupled with the loss of several genes that normally suppress tumors.
Abstract: Because most colorectal carcinomas appear to arise from adenomas, studies of different stages of colorectal neoplasia may shed light on the genetic alterations involved in tumor progression. We looked for four genetic alterations (ras-gene mutations and allelic deletions of chromosomes 5, 17, and 18) in 172 colorectal-tumor specimens representing various stages of neoplastic development. The specimens consisted of 40 predominantly early-stage adenomas from 7 patients with familial adenomatous polyposis, 40 adenomas (19 without associated foci of carcinoma and 21 with such foci) from 33 patients without familial polyposis, and 92 carcinomas resected from 89 patients. We found that ras-gene mutations occurred in 58 percent of adenomas larger than 1 cm and in 47 percent of carcinomas. However, ras mutations were found in only 9 percent of adenomas under 1 cm in size. Sequences on chromosome 5 that are linked to the gene for familial adenomatous polyposis were not lost in adenomas from the patients with polyposis but were lost in 29 to 35 percent of adenomas and carcinomas, respectively, from other patients. A specific region of chromosome 18 was deleted frequently in carcinomas (73 percent) and in advanced adenomas (47 percent) but only occasionally in earlier-stage adenomas (11 to 13 percent). Chromosome 17p sequences were usually lost only in carcinomas (75 percent). The four molecular alterations accumulated in a fashion that paralleled the clinical progression of tumors. These results are consistent with a model of colorectal tumorigenesis in which the steps required for the development of cancer often involve the mutational activation of an oncogene coupled with the loss of several genes that normally suppress tumorigenesis.

6,309 citations