Nuclear Receptor NR1H3 in Familial Multiple Sclerosis

Wang, Zhe; Sadovnick, A. Dessa; Traboulsee, Anthony; Ross, Jay P.; Bernales, Cecily Q.; Encarnacion, Mary Joy; Yee, Irene M.; Lemos, Madonna de; Greenwood, Talitha; Lee, Joshua D.; Wright, Galen E.B.; Ross, Colin J.; Zhang, Si; Song, Weihong; Vilariño‐Güell, Carles

doi:10.1016/j.neuron.2016.04.039

Cited by 81 publications

(94 citation statements)

References 36 publications

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“…NGS can easily lead to a false-positive being associated with disease if the genetic hypothesis is flawed, population genetics is neglected, or experimental validation is insufficient (e.g. the recent report of a presumed novel disease-causing mutation in seven patients with multiple sclerosis from two multiplex families) (44, 45). Only in rare cases of phenotypic and genetic homogeneity can a strong suspicion of causality be established by genetic means alone (e.g.…”

Section: Validating Genetic Findings Experimentallymentioning

confidence: 99%

Exome and genome sequencing for inborn errors of immunity

Meyts

Bosch

Bolze

et al. 2016

Journal of Allergy and Clinical Immunology

167

148

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The advent of next generation sequencing (NGS) in 2010 has transformed medicine and particularly the growing field of monogenic inborn errors of immunity, including primary immunodeficiencies (PID). NGS has facilitated the discovery of novel disease-causing genes and the genetic diagnosis of patients with PID. Whole-exome sequencing (WES) is presently the most cost-effective approach for PID research and diagnostics, though whole genome sequencing (WGS) offers several advantages. The scientific or diagnostic challenge consists in selecting one or two candidate variants among thousands of NGS calls. Variant- and gene-level computational methods as well as immunological hypotheses can help to narrow down this genome-wide search. The key to success is a well-informed genetic hypothesis on three key aspects: mode of inheritance, clinical penetrance, and genetic heterogeneity of the condition. This determines the search strategy and the frequency cut-offs for candidate alleles. Subsequent functional validation of the disease-causing effect of the candidate variant is critical. Even the most up-to-date dry lab cannot clinch this validation without a seasoned wet lab. The multifariousness of variations entails an experimental rigor even greater than traditional Sanger sequencing-based approaches, in order not to assign PID to false positives. Finding the needle in the haystack takes patience, prudence, and discernment.

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Section: Validating Genetic Findings Experimentallymentioning

confidence: 99%

Exome and genome sequencing for inborn errors of immunity

Meyts

Bosch

Bolze

et al. 2016

Journal of Allergy and Clinical Immunology

167

148

View full text Add to dashboard Cite

show abstract

“…However, two major issues face the field of human genetics. First, erroneous assignment of a gene as disease-associated can occur if rigorous validation and statistical analyses are not performed [32]. Second, once a gene is implicated in disease based on a strong genetic argument, newly identified variants can be erroneously attributed as ‘pathogenic’, which can be overlooked if the variant was coincidentally identified in a patient with the correct disease phenotype.…”

Section: Ars Variant Identification and Validationmentioning

confidence: 99%

Predicting the pathogenicity of aminoacyl-tRNA synthetase mutations

Oprescu

Griffin

Beg

et al. 2017

Methods

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Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed, essential enzymes responsible for charging tRNA with cognate amino acids—the first step in protein synthesis. ARSs are required for protein translation in the cytoplasm and mitochondria of all cells. Surprisingly, mutations in 28 of the 37 nuclear-encoded human ARS genes have been linked to a variety of recessive and dominant tissue-specific disorders. Current data sustains that impaired enzyme function is a robust predictor of the pathogenicity of ARS mutations. However, experimental model systems that distinguish between pathogenic and non-pathogenic ARS variants are required for implicating newly identified ARS mutations in disease. Here, we outline strategies to assist in predicting the pathogenicity of ARS variants and urge cautious evaluation of genetic and functional data prior to linking an ARS mutation to a human disease phenotype.

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“…The more accepted pathogenic hypothesis is that MS may be the result of a particular combination of genetic predisposition and action of unknown environmental factors that, when present in the same individual, may lead to this dysfunction of the neurological system 2,3,4 . The involvement of the neurological system can cause the patient with MS to suffer relapses.…”

Section: Introductionmentioning

confidence: 99%

Influence of particulate matter and meteorological conditions on multiple sclerosis relapse: a preliminary study in São Paulo, Brazil

Diniz¹,

Frony-Macedo²,

Piacenti-Silva³

2017

Arch Health Invest

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Introduction: Multiple sclerosis (MS) is a chronic, inflammatory, and demyelinating disease of the central nervous system, which in some cases may be characterized by recurrent relapses of inflammation that cause mild to severe neurological disability. Some studies around the world have associated the increase of systemic inflammatory responses and neuro-inflammation of patients with exposure to high levels of particulate matter (PM 10 ) and certain conditions of temperature and humidity. Materials and methods: The objective of this study was to verify the influence of the concentration of PM 10 and meteorological variables (air temperature and relative humidity) on the number of hospitalizations for MS in the city of São Paulo. Data from 2008 to 2016, which passed through descriptive statistics and inferences, were used as multiple linear regression models. Results: The models obtained indicated a positive relation (p < 0.01) in the number of hospitalizations with the increase of PM 10 and relative humidity, showing that 31.23% of hospital admissions can be explained by these variables. Conclusion: These results are important, since there are no other studies from Brazil that correlate meteorological and air quality variables with MS. Descriptors: Air Pollution; Multiple Sclerosis; Linear Models. ResumoIntrodução: A Esclerose Múltipla (EM) é uma doença crônica, inflamatória e desmielinizante do sistema nervoso central, que em alguns casos pode ser caracterizada por surtos recorrentes de inflamação que causam leve a grave deficiência neurológica. Alguns estudos em todo o mundo têm associado o aumento de respostas inflamatórias sistêmicas e neuroinflamação de pacientes quando expostos a altos níveis de material particulado (MP 10 ) e certas condições de temperatura e umidade. Material e Método: O objetivo deste estudo foi verificar a influência da concentração de material particulado (MP 10 ) e das variáveis meteorológicas (temperatura do ar e umidade relativa) sobre o número de internações por EM na cidade de São Paulo. Para isso foram utilizados dados destas no período de 2008 a 2016, os quais passaram por estatísticas descritivas e inferencias, como modelos de regressão linear múltipla. Resultados: Os modelos obtidos indicaram relação positiva (p <0,01) no número de internações com o aumento do material particulado MP 10 e umidade relativa, demonstrando que 31,23% das internações hospitalares podem ser explicadas por essas variáveis. Conclusão: Esses resultados são importantes, pois até agora, em nosso conhecimento, no Brasil não existem estudos que correlacionem as variáveis meteorológicas e de qualidade do ar com a Esclerose Múltipla. Descritores: Poluição do Ar; Esclerose Múltipla; Modelos Lineares. ResumenIntroducción: La esclerosis múltiple (EM) es una enfermedad del sistema crónica, inflamatoria y desmielinizante nervioso central, que en algunos casos puede ser caracterizada mediante recaídas recurrentes de inflamación causando leve a déficit neurológico grave. Algunos estudios de todo el mundo q...

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Nuclear Receptor NR1H3 in Familial Multiple Sclerosis

Cited by 81 publications

References 36 publications

Exome and genome sequencing for inborn errors of immunity

Exome and genome sequencing for inborn errors of immunity

Predicting the pathogenicity of aminoacyl-tRNA synthetase mutations

Influence of particulate matter and meteorological conditions on multiple sclerosis relapse: a preliminary study in São Paulo, Brazil

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