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1.
Dis Model Mech ; 14(10)2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34477842

RESUMO

Down syndrome (DS), trisomy 21, results in many complex phenotypes including cognitive deficits, heart defects and craniofacial alterations. Phenotypes arise from an extra copy of human chromosome 21 (Hsa21) genes. However, these dosage-sensitive causative genes remain unknown. Animal models enable identification of genes and pathological mechanisms. The Dp1Tyb mouse model of DS has an extra copy of 63% of Hsa21-orthologous mouse genes. In order to establish whether this model recapitulates DS phenotypes, we comprehensively phenotyped Dp1Tyb mice using 28 tests of different physiological systems and found that 468 out of 1800 parameters were significantly altered. We show that Dp1Tyb mice have wide-ranging DS-like phenotypes, including aberrant erythropoiesis and megakaryopoiesis, reduced bone density, craniofacial changes, altered cardiac function, a pre-diabetic state, and deficits in memory, locomotion, hearing and sleep. Thus, Dp1Tyb mice are an excellent model for investigating complex DS phenotype-genotype relationships for this common disorder.

2.
Curr Protoc Mouse Biol ; 10(3): e81, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32865891

RESUMO

The 24-hr cycle of activity and sleep provides perhaps the most familiar example of circadian rhythms. In mammals, circadian activity rhythms are generated by a master biological clock located in the hypothalamic suprachiasmatic nuclei (SCN). This clock is synchronized (entrained) to the external light environment via light input from retinal photoreceptors. However, sleep is not a simple circadian output and also is regulated by a homeostatic process whereby extended wakefulness increases the need for subsequent sleep. As such, the amount and distribution of sleep depends upon the interaction between both circadian and homeostatic processes. Moreover, the study of circadian activity and sleep is not confined only to these specialized fields. Sleep and circadian rhythm disruption is common in many conditions, ranging from neurological and metabolic disorders to aging. Such disruption is associated with a range of negative consequences including cognitive impairment and mood disorders, as well as immune and metabolic dysfunction. As circadian activity and sleep are hallmarks of normal healthy physiology, they also provide valuable welfare indicators. However, traditional methods for the monitoring of circadian rhythms and sleep in mice can require separate specialized resources as well as significant expertise. Here, we outline a low-cost, non-invasive, and open-source method for the simultaneous assessment of circadian activity and sleep in mice. This protocol describes both the assembly of the hardware used and the capture and analysis of data without the need for expertise in electronics or data processing. © 2020 Wiley Periodicals LLC. Basic Protocol: Assembly of a PIR system for basic activity and sleep recordings Alternate Protocol: Data collection using Raspberry Pi Support Protocol: Circadian analysis using PIR sensors.


Assuntos
Ritmo Circadiano/fisiologia , Raios Infravermelhos , Sono/fisiologia , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL
3.
Sci Adv ; 6(33): eabb3567, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32851175

RESUMO

Switches between global sleep and wakefulness states are believed to be dictated by top-down influences arising from subcortical nuclei. Using forward genetics and in vivo electrophysiology, we identified a recessive mouse mutant line characterized by a substantially reduced propensity to transition between wake and sleep states with an especially pronounced deficit in initiating rapid eye movement (REM) sleep episodes. The causative mutation, an Ile102Asn substitution in the synaptic vesicular protein, VAMP2, was associated with morphological synaptic changes and specific behavioral deficits, while in vitro electrophysiological investigations with fluorescence imaging revealed a markedly diminished probability of vesicular release in mutants. Our data show that global shifts in the synaptic efficiency across brain-wide networks leads to an altered probability of vigilance state transitions, possibly as a result of an altered excitability balance within local circuits controlling sleep-wake architecture.

4.
FASEB J ; 32(8): 4302-4314, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29561690

RESUMO

Cryptochromes 1 and 2 (CRY1/2) are key components of the negative limb of the mammalian circadian clock. Like many peripheral tissues, Cry1 and -2 are expressed in the retina, where they are thought to play a role in regulating rhythmic physiology. However, studies differ in consensus as to their localization and function, and CRY1 immunostaining has not been convincingly demonstrated in the retina. Here we describe the expression and function of CRY1 and -2 in the mouse retina in both sexes. Unexpectedly, we show that CRY1 is expressed throughout all retinal layers, whereas CRY2 is restricted to the photoreceptor layer. Retinal period 2::luciferase recordings from CRY1-deficient mice show reduced clock robustness and stability, while those from CRY2-deficient mice show normal, albeit long-period, rhythms. In functional studies, we then investigated well-defined rhythms in retinal physiology. Rhythms in the photopic electroretinogram, contrast sensitivity, and pupillary light response were all severely attenuated or abolished in CRY1-deficient mice. In contrast, these physiological rhythms are largely unaffected in mice lacking CRY2, and only photopic electroretinogram rhythms are affected. Together, our data suggest that CRY1 is an essential component of the mammalian retinal clock, whereas CRY2 has a more limited role.-Wong, J. C. Y., Smyllie, N. J., Banks, G. T., Pothecary, C. A., Barnard, A. R., Maywood, E. S., Jagannath, A., Hughes, S., van der Horst, G. T. J., MacLaren, R. E., Hankins, M. W., Hastings, M. H., Nolan, P. M., Foster, R. G., Peirson, S. N. Differential roles for cryptochromes in the mammalian retinal clock.


Assuntos
Criptocromos/metabolismo , Mamíferos/metabolismo , Mamíferos/fisiologia , Retina/metabolismo , Retina/fisiologia , Animais , Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Eletrorretinografia/métodos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Fotorreceptoras/metabolismo , Células Fotorreceptoras/fisiologia
5.
J Neurosci ; 33(17): 7145-53, 2013 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-23616524

RESUMO

The circadian clock of the suprachiasmatic nucleus (SCN) drives daily rhythms of behavior. Cryptochromes (CRYs) are powerful transcriptional repressors within the molecular negative feedback loops at the heart of the SCN clockwork, where they periodically suppress their own expression and that of clock-controlled genes. To determine the differential contributions of CRY1 and CRY2 within circadian timing in vivo, we exploited the N-ethyl-N-nitrosourea-induced afterhours mutant Fbxl3(Afh) to stabilize endogenous CRY. Importantly, this was conducted in CRY2- and CRY1-deficient mice to test each CRY in isolation. In both CRY-deficient backgrounds, circadian rhythms of wheel-running and SCN bioluminescence showed increased period length with increased Fbxl3(Afh) dosage. Although both CRY proteins slowed the clock, CRY1 was significantly more potent than CRY2, and in SCN slices, CRY1 but not CRY2 prolonged the interval of transcriptional suppression. Selective CRY-stabilization demonstrated that both CRYs are endogenous transcriptional repressors of clock-controlled genes, but again CRY1 was preeminent. Finally, although Cry1(-/-);Cry2(-/-) mice were behaviorally arrhythmic, their SCN expressed short period (~18 h) rhythms with variable stability. Fbxl3(Afh/Afh) had no effect on these CRY-independent rhythms, confirming its circadian action is mediated exclusively via CRYs. Thus, stabilization of both CRY1 and CRY2 are necessary and sufficient to explain circadian period lengthening by Fbxl3(Afh/Afh). Both CRY proteins dose-dependently lengthen the intrinsic, high-frequency SCN rhythm, and CRY2 also attenuates the more potent period-lengthening effects of CRY1. Incorporation of CRY-mediated transcriptional feedback thus confers stability to intrinsic SCN oscillations, establishing periods between 18 and 29 h, as determined by selective contributions of CRY1 and CRY2.


Assuntos
Relógios Circadianos/genética , Criptocromos/fisiologia , Proteínas F-Box/fisiologia , Mutação/fisiologia , Núcleo Supraquiasmático/fisiologia , Animais , Animais Recém-Nascidos , Ritmo Circadiano/genética , Criptocromos/genética , Proteínas F-Box/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Técnicas de Cultura de Órgãos
6.
J Neurosci ; 31(14): 5483-94, 2011 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-21471385

RESUMO

The cytoplasmic dynein complex is fundamentally important to all eukaryotic cells for transporting a variety of essential cargoes along microtubules within the cell. This complex also plays more specialized roles in neurons. The complex consists of 11 types of protein that interact with each other and with external adaptors, regulators and cargoes. Despite the importance of the cytoplasmic dynein complex, we know comparatively little of the roles of each component protein, and in mammals few mutants exist that allow us to explore the effects of defects in dynein-controlled processes in the context of the whole organism. Here we have taken a genotype-driven approach in mouse (Mus musculus) to analyze the role of one subunit, the dynein light intermediate chain 1 (Dync1li1). We find that, surprisingly, an N235Y point mutation in this protein results in altered neuronal development, as shown from in vivo studies in the developing cortex, and analyses of electrophysiological function. Moreover, mutant mice display increased anxiety, thus linking dynein functions to a behavioral phenotype in mammals for the first time. These results demonstrate the important role that dynein-controlled processes play in the correct development and function of the mammalian nervous system.


Assuntos
Comportamento Animal/fisiologia , Dineínas do Citoplasma/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Fenótipo , Mutação Puntual/genética , Animais , Animais Recém-Nascidos , Asparagina/genética , Contagem de Células/métodos , Células Cultivadas , Córtex Cerebral/citologia , Dendritos/genética , Embrião de Mamíferos , Feminino , Fibroblastos/fisiologia , Fibroblastos/ultraestrutura , Gânglios Espinais/citologia , Proteínas de Fluorescência Verde/genética , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/genética , Proteínas do Tecido Nervoso , Condução Nervosa/genética , Neurônios/classificação , Neurônios/citologia , Neurônios/fisiologia , Transporte Proteico/efeitos dos fármacos , Transporte Proteico/genética , Desempenho Psicomotor , Estatísticas não Paramétricas , Tirosina/genética , Levantamento de Peso/fisiologia
7.
Curr Protoc Mouse Biol ; 1(3): 369-81, 2011 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26068996

RESUMO

In most organisms, physiological variables are regulated by an internal clock. This endogenous circadian (∼24-hr) clock enables organisms to anticipate daily environmental changes and modify behavioral and physiological functions appropriately. Processes regulated by the circadian clock include sleep-wake and locomotor activity, core body temperature, metabolism, water/food intake, and available hormone levels. At the core of the mammalian circadian system are molecular oscillations within the hypothalamic suprachiasmatic nucleus. These oscillations are modifiable by signals from the environment (so called zeitgebers or time-givers) and, once integrated within the suprachiasmatic nucleus, are conveyed to remote neural circuits where output rhythms are regulated. Disrupting any of a number of neural processes can affect how rhythms are generated and relayed to the periphery and disturbances in circadian/entrainment parameters are associated with numerous human conditions. These non-invasive protocols can be used to determine whether circadian/entrainment parameters are affected in mouse mutants or treatment groups. Curr. Protoc. Mouse Biol. 1:369-381 © 2011 by John Wiley & Sons, Inc.

8.
Nat Genet ; 42(12): 1086-92, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21076408

RESUMO

Genome-wide association studies have identified SNPs within FTO, the human fat mass and obesity-associated gene, that are strongly associated with obesity. Individuals homozygous for the at-risk rs9939609 A allele weigh, on average, ~3 kg more than individuals with the low-risk T allele. Mice that lack FTO function and/or Fto expression display increased energy expenditure and a lean phenotype. We show here that ubiquitous overexpression of Fto leads to a dose-dependent increase in body and fat mass, irrespective of whether mice are fed a standard or a high-fat diet. Our results suggest that increased body mass results primarily from increased food intake. Mice with increased Fto expression on a high-fat diet develop glucose intolerance. This study provides the first direct evidence that increased Fto expression causes obesity in mice.


Assuntos
Comportamento Alimentar/fisiologia , Obesidade/genética , Oxo-Ácido-Liases/metabolismo , Adiposidade/efeitos dos fármacos , Adiposidade/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Animais , Área Sob a Curva , Temperatura Corporal , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/genética , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/farmacologia , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/genética , Comportamento Alimentar/efeitos dos fármacos , Feminino , Glucose/metabolismo , Teste de Tolerância a Glucose , Homeostase/genética , Masculino , Camundongos , Oxigenases de Função Mista , Modelos Animais , Atividade Motora/efeitos dos fármacos , Obesidade/sangue , Oxo-Ácido-Liases/genética
9.
PLoS One ; 5(7): e11682, 2010 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-20657784

RESUMO

BACKGROUND: Intracellular transport of cargoes including organelles, vesicles, signalling molecules, protein complexes, and RNAs, is essential for normal function of eukaryotic cells. The cytoplasmic dynein complex is an important motor that moves cargos along microtubule tracks within the cell. In mammals this multiprotein complex includes dynein intermediate chains 1 and 2 which are encoded by two genes, Dync1i1 and Dync1i2. These proteins are involved in dynein cargo binding and dynein complexes with different intermediate chains bind to specific cargoes, although the mechanisms to achieve this are not known. The DYNC1I1 and DYNC1I2 proteins are translated from different splice isoforms, and specific forms of each protein are essential for the function of different dynein complexes in neurons. METHODOLOGY/PRINCIPAL FINDINGS: Here we have undertaken a systematic survey of the dynein intermediate chain splice isoforms in mouse, basing our study on mRNA expression patterns in a range of tissues, and on bioinformatics analysis of mouse, rat and human genomic and cDNA sequences. We found a complex pattern of alternative splicing of both dynein intermediate chain genes, with maximum complexity in the embryonic and adult nervous system. We have found novel transcripts, including some with orthologues in human and rat, and a new promoter and alternative non-coding exon 1 for Dync1i2. CONCLUSIONS/SIGNIFICANCE: These data, including the cloned isoforms will be essential for understanding the role of intermediate chains in the cytoplasmic dynein complex, particularly their role in cargo binding within individual tissues including different brain regions.


Assuntos
Citoplasma/metabolismo , Dineínas/metabolismo , Isoformas de Proteínas/metabolismo , Processamento Alternativo/genética , Processamento Alternativo/fisiologia , Animais , Biologia Computacional , Dineínas/genética , Humanos , Camundongos , Isoformas de Proteínas/genética , Ratos
10.
PLoS One ; 4(7): e6218, 2009 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-19593442

RESUMO

BACKGROUND: In humans, mutations in the enzyme glycyl-tRNA synthetase (GARS) cause motor and sensory axon loss in the peripheral nervous system, and clinical phenotypes ranging from Charcot-Marie-Tooth neuropathy to a severe infantile form of spinal muscular atrophy. GARS is ubiquitously expressed and may have functions in addition to its canonical role in protein synthesis through catalyzing the addition of glycine to cognate tRNAs. METHODOLOGY/PRINCIPAL FINDINGS: We have recently described a new mouse model with a point mutation in the Gars gene resulting in a cysteine to arginine change at residue 201. Heterozygous Gars(C201R/+) mice have locomotor and sensory deficits. In an investigation of genetic mutations that lead to death of motor and sensory neurons, we have crossed the Gars(C201R/+) mice to two other mutants: the TgSOD1(G93A) model of human amyotrophic lateral sclerosis and the Legs at odd angles mouse (Dync1h1(Loa)) which has a defect in the heavy chain of the dynein complex. We found the Dync1h1(Loa/+);Gars(C201R/+) double heterozygous mice are more impaired than either parent, and this is may be an additive effect of both mutations. Surprisingly, the Gars(C201R) mutation significantly delayed disease onset in the SOD1(G93A);Gars(C201R/+) double heterozygous mutant mice and increased lifespan by 29% on the genetic background investigated. CONCLUSIONS/SIGNIFICANCE: These findings raise intriguing possibilities for the study of pathogenetic mechanisms in all three mouse mutant strains.


Assuntos
Dineínas/fisiologia , Glicina-tRNA Ligase/metabolismo , Doença dos Neurônios Motores/enzimologia , Mutação , Superóxido Dismutase/metabolismo , Animais , Sequência de Bases , Primers do DNA , Modelos Animais de Doenças , Dineínas/genética , Feminino , Glicina-tRNA Ligase/genética , Heterozigoto , Masculino , Camundongos , Camundongos Mutantes , Doença dos Neurônios Motores/genética , Doença dos Neurônios Motores/metabolismo , Fenótipo , Superóxido Dismutase/genética
11.
Dis Model Mech ; 2(7-8): 359-73, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19470612

RESUMO

Mutations in the enzyme glycyl-tRNA synthetase (GARS) cause motor and sensory axon loss in the peripheral nervous system in humans, described clinically as Charcot-Marie-Tooth type 2D or distal spinal muscular atrophy type V. Here, we characterise a new mouse mutant, Gars(C201R), with a point mutation that leads to a non-conservative substitution within GARS. Heterozygous mice with a C3H genetic background have loss of grip strength, decreased motor flexibility and disruption of fine motor control; this relatively mild phenotype is more severe on a C57BL/6 background. Homozygous mutants have a highly deleterious set of features, including movement difficulties and death before weaning. Heterozygous animals have a reduction in axon diameter in peripheral nerves, slowing of nerve conduction and an alteration in the recovery cycle of myelinated axons, as well as innervation defects. An assessment of GARS levels showed increased protein in 15-day-old mice compared with controls; however, this increase was not observed in 3-month-old animals, indicating that GARS function may be more crucial in younger animals. We found that enzyme activity was not reduced detectably in heterozygotes at any age, but was diminished greatly in homozygous mice compared with controls; thus, homozygous animals may suffer from a partial loss of function. The Gars(C201R) mutation described here is a contribution to our understanding of the mechanism by which mutations in tRNA synthetases, which are fundamentally important, ubiquitously expressed enzymes, cause axonopathy in specific sets of neurons.


Assuntos
Doença de Charcot-Marie-Tooth/genética , Glicina-tRNA Ligase/genética , Neurônios Motores/patologia , Mutação , Células Receptoras Sensoriais/patologia , Sequência de Aminoácidos , Animais , Modelos Animais de Doenças , Etilnitrosoureia/farmacologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Dados de Sequência Molecular , Fenótipo , Homologia de Sequência de Aminoácidos
12.
Proc Natl Acad Sci U S A ; 106(16): 6706-11, 2009 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-19351902

RESUMO

The hereditary ataxias are a complex group of neurological disorders characterized by the degeneration of the cerebellum and its associated connections. The molecular mechanisms that trigger the loss of Purkinje cells in this group of diseases remain incompletely understood. Here, we report a previously undescribed dominant mouse model of cerebellar ataxia, moonwalker (Mwk), that displays motor and coordination defects and loss of cerebellar Purkinje cells. Mwk mice harbor a gain-of-function mutation (T635A) in the Trpc3 gene encoding the nonselective transient receptor potential cation channel, type C3 (TRPC3), resulting in altered TRPC3 channel gating. TRPC3 is highly expressed in Purkinje cells during the phase of dendritogenesis. Interestingly, growth and differentiation of Purkinje cell dendritic arbors are profoundly impaired in Mwk mice. Our findings define a previously unknown role for TRPC3 in both dendritic development and survival of Purkinje cells, and provide a unique mechanism underlying cerebellar ataxia.


Assuntos
Ataxia Cerebelar/patologia , Mutação Puntual/genética , Células de Purkinje/patologia , Canais de Cátion TRPC/genética , Sequência de Aminoácidos , Animais , Diferenciação Celular , Ataxia Cerebelar/fisiopatologia , Dendritos/patologia , Ativação do Canal Iônico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Mutantes Neurológicos , Dados de Sequência Molecular , Atividade Motora , Fosforilação , Canais de Cátion TRPC/química
13.
Mamm Genome ; 19(5): 299-305, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18592312

RESUMO

In 2006 the protein TDP-43 was identified as the major ubiquitinated component deposited in the inclusion bodies found in two human neurodegenerative diseases, amyotrophic lateral sclerosis and frontotemporal lobar degeneration. The pathogenesis of both disorders is unclear, although they are related by having some overlap of symptoms and now by the shared histopathology of TDP-43 deposition. Now, in 2008, several papers have been published in quick succession describing mutations in the TDP-43 gene, showing they can be a primary cause of amyotrophic lateral sclerosis. There are many precedents in neurodegenerative disease in which rare single-gene mutations have given great insight into understanding disease processes, which is why the TDP-43 mutations are potentially very important.


Assuntos
Proteínas de Ligação a DNA/genética , Doenças Neurodegenerativas/genética , Animais , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/fisiologia , Doenças Genéticas Inatas/genética , Humanos , Modelos Biológicos , Mutação/fisiologia , Placa Amiloide/genética
14.
Genome Biol ; 9(3): 214, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18373888

RESUMO

A new mouse mutation, Sprawling, highlights an essential role for the dynein heavy chain in sensory neuron function, but it lacks the ability of other known heavy-chain mutations to ameliorate neurodegeneration due to defective superoxide dismutase.


Assuntos
Dineínas/genética , Doenças Neurodegenerativas/genética , Esclerose Amiotrófica Lateral/genética , Animais , Citoplasma/enzimologia , Dineínas do Citoplasma , Dineínas/metabolismo , Humanos , Camundongos , Camundongos Knockout , Mutação , Neurônios Aferentes/fisiologia
15.
Trends Mol Med ; 13(12): 512-9, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17981508

RESUMO

The year 2009 is the 100th anniversary of the founding of the first inbred strain of mouse, called DBA. During the last 100 years, inbred strains have proved their value for biomedical research and the number of such strains has mushroomed to over 450, each with different genotypic and phenotypic characteristics and useful for the study of disease and normal function. However, although inbred strains are stable, they are not fixed entities and researchers need to be aware of the phenomena of new mutations and of genetic drift, which occur within all mouse colonies. If the mutations are what we term in this review 'quiet mutations', then they might result in rather unexpected and sometimes tremendously valuable results. Here, we discuss these phenomena and look at how new genomic technologies might help us to detect 'quiet mutations' and use them to our advantage.


Assuntos
Mutação , Animais , Genótipo , Camundongos , Camundongos Endogâmicos , Fenótipo
16.
Brain ; 130(Pt 9): 2292-301, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17439985

RESUMO

Sporadic amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, most likely results from complex genetic and environmental interactions. Although a number of association studies have been performed in an effort to find genetic components of sporadic ALS, most of them resulted in inconsistent findings due to a small number of genes investigated in relatively small sample sizes, while the replication of results was rarely attempted. Defects in retrograde axonal transport, vesicle trafficking and xenobiotic metabolism have been implicated in neurodegeneration and motor neuron death both in human disease and animal models. To assess the role of common genetic variation in these pathways in susceptibility to sporadic ALS, we performed a pathway-based candidate gene case-control association study with replication. Furthermore, we determined reliability of whole genome amplified DNA in a large-scale association study. In the first stage of the study, 1277 putative functional and tagging SNPs in 134 genes spanning 8.7 Mb were genotyped in 822 British sporadic ALS patients and 872 controls using whole genome amplified DNA. To detect variants with modest effect size and discriminate among false positive findings 19 SNPs showing a trend of association in the initial screen were genotyped in a replication sample of 580 German sporadic ALS patients and 361 controls. We did not detect strong evidence of association with any of the genes investigated in the discovery sample (lowest uncorrected P-value 0.00037, lowest permutation corrected P-value 0.353). None of the suggestive associations was replicated in a second sample, further excluding variants with moderate effect size. We conclude that common variation in the investigated pathways is unlikely to have a major effect on susceptibility to sporadic ALS. The genotyping efficiency was only slightly decreased ( approximately 1%) and genotyping quality was not affected using whole genome amplified DNA. It is reliable for large scale genotyping studies of diseases such as ALS, where DNA sample collections are limited because of low disease prevalence and short survival time.


Assuntos
Esclerose Amiotrófica Lateral/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/fisiopatologia , Transporte Axonal/genética , Estudos de Casos e Controles , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Genoma Humano , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Vesículas Transportadoras/metabolismo , Xenobióticos/metabolismo
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