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.D.; Zhang, Si; Song, Weihong; Vilariño‐Güell, Carles

doi:10.1016/j.neuron.2016.09.028

Cited by 17 publications

(9 citation statements)

References 32 publications

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“…A). The pattern of disease inheritance in this family is suggestive of an autosomal‐dominant trait with reduced penetrance; therefore, only rare heterozygote coding substitutions identified in all affected individuals were considered potentially pathogenic; detailed methodology has been previously described (Wang et al., ). Exome analysis identified a total of 82,073 variants across all five affected subjects, with 3,548 autosomal heterozygote genotypes being observed in all family members examined.…”

Section: Resultsmentioning

confidence: 99%

“…Two‐point logarithm of odds (LOD) score was obtained with MLINK assuming a dominant model, with a fully penetrant mutation and without phenocopies, as previously described (Chartier‐Harlin et al., ; Ott, ; Wang et al., ). The deleterious allele was defined with a 0.0001 frequency, and the marker‐allele frequencies were determined empirically from genotyped individuals within the family.…”

Section: Methodsmentioning

confidence: 99%

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Purinergic receptorsP2RX4andP2RX7in familial multiple sclerosis

Sadovnick

Traboulsee

et al. 2017

Human Mutation

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Genetic variants in the purinergic receptors P2RX4 and P2RX7 have been shown to affect susceptibility to multiple sclerosis (MS). In this study we set out to evaluate whether rare coding variants of major effect could also be identified in these purinergic receptors. Sequencing analysis of P2RX4 and P2RX7 in 193 MS patients and 100 controls led to the identification of a rare three variant haplotype (P2RX7 rs140915863:C>T (p.T205M), P2RX7 rs201921967:A>G (p.N361S) and P2RX4 rs765866317:G>A (p.G135S)) segregating with disease in a multi-incident family with six family members diagnosed with MS (LOD=3.07). Functional analysis of this haplotype in HEK293 cells revealed impaired P2X7 surface expression (p<0.01), resulting in over 95% inhibition of ATP-induced pore function (p<0.001) and a marked reduction in phagocytic ability (p<0.05). In addition, transfected cells showed 40% increased peak ATP-induced inward current (p<0.01), and a greater Ca 2+ response to the P2X4 135S variant compared to wild type (p<0.0001). Our study nominates rare genetic variants in P2RX4 and P2RX7 as major genetic contributors to disease, further supporting a role for these purinergic receptors in MS and suggesting the disruption of transmembrane cation channels leading to impairment of phagocytosis as the pathological mechanisms of disease.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Purinergic receptorsP2RX4andP2RX7in familial multiple sclerosis

Sadovnick

Traboulsee

et al. 2017

Human Mutation

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“…In MS, as in most other neurodegenerative diseases, genetic influences play an important role as well. However, unlike in a number of other neurodegenerative disorders, where specific mutations have been identified as causes for at least a subset of these, such mutations have yet to be identified in MS 18– 20 . Instead, a large number of susceptibility loci, the vast majority of which are related to immune function, have been found through genome-wide association studies (GWASs) 20– 27 .…”

Section: The Genetics Of Msmentioning

confidence: 99%

Recent advances in understanding multiple sclerosis

Stys

Tsutsui

2019

F1000Res

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Emerging data point to important contributions of both autoimmune inflammation and progressive degeneration in the pathophysiology of multiple sclerosis (MS). Unfortunately, after decades of intensive investigation, the fundamental cause remains unknown. A large body of research on the immunobiology of MS has resulted in a variety of anti-inflammatory therapies that are highly effective at reducing brain inflammation and clinical/radiological relapses. However, despite potent suppression of inflammation, benefit in the more important and disabling progressive phase is extremely limited; thus, progressive MS has emerged as the greatest challenge for the MS research and clinical communities. Data obtained over the years point to a complex interplay between environment (e.g., the near-absolute requirement of Epstein–Barr virus exposure), immunogenetics (strong associations with a large number of immune genes), and an ever more convincing role of an underlying degenerative process resulting in demyelination (in both white and grey matter regions), axonal and neuro-synaptic injury, and a persistent innate inflammatory response with a seemingly diminishing role of T cell–mediated autoimmunity as the disease progresses. Together, these observations point toward a primary degenerative process, one whose cause remains unknown but one that entrains a nearly ubiquitous secondary autoimmune response, as a likely sequence of events underpinning this disease. Here, we briefly review what is known about the potential pathophysiological mechanisms, focus on progressive MS, and discuss the two main hypotheses of MS pathogenesis that are the topic of vigorous debate in the field: whether primary autoimmunity or degeneration lies at the foundation. Unravelling this controversy will be critically important for developing effective new therapies for the most disabling later phases of this disease.

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“…Recently, Wang et al. reported that they discovered the NR1H3 p.Arg415Gln mutation in seven MS patients from two multi‐case families with severe and progressive disease course, and concluded that it is the first pathogenic mutation for MS . However, the finding was not replicated in the datasets of the International MS Genetics Consortium with a 13‐fold larger sample size .…”

Section: What Is Next For Ms Genetics?mentioning

confidence: 99%

Genetics in multiple sclerosis: Updates in the era of big data

Isobe

2018

Clinical & Exp Neuroim

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Multiple sclerosis is a complex disease where both genetics and environmental factors play critical roles in its susceptibility. The contribution of genetics has been proven by familial studies, but there still exists missing heritability. Big data science has been a novel approach in research, including multiple sclerosis genetics, and multiple tools to handle those big data have been developed for researchers in different fields: from tools with a user‐friendly graphical user interface to more professional tools with a text user interface. In this era of big data, it is important to accelerate collaborative studies with researchers of distinct professions, such as bioinformaticians, statisticians, geneticists and computational biologists.

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Nuclear Receptor NR1H3 in Familial Multiple Sclerosis

Cited by 17 publications

References 32 publications

Purinergic receptorsP2RX4andP2RX7in familial multiple sclerosis

Purinergic receptorsP2RX4andP2RX7in familial multiple sclerosis

Recent advances in understanding multiple sclerosis

Genetics in multiple sclerosis: Updates in the era of big data

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