NR1H3 p.Arg415Gln Is Not Associated to Multiple Sclerosis Risk

Antel, Jack; Ban, Masashi; Baranzini, Sergio E.; Barcellos, Lisa F.; Barizzone, Nadia; Beecham, Ashley; Berge, Tone; Bernardinelli, Luisa; Booth, David R.; Bos, Steffan D.; Buck, Dorothea; Butkiewicz, Mariusz; Celius, Elisabeth Gulowsen; Comabella, Manuel; Compston, Alastair; Dedham, Katrina; Cotsapas, Chris; S, Alfonso; Jager, Phil De; Dubois, Bénédicte; Duquette, Pierre; Fontaine, Bertrand; Gasperi, Christiane; Gil, Elia; Goris, An; Gourraud, Pierre-Antoine; Graetz, Christiane; Gyllenberg, Alexandra; Hadjigeorgiou, Georgios M.; Hafler, David A.; Hribko, Deanna; Haines, Jonathan L.; Harbo, Hanne F.; Hauser, Stephen L.; Warto, Shannon; Hawkins, Clive; Hemmer, Bernhard; Henry, R; Hintzen, Rogier Q.; Horáková, Dana; Ivinson, Adrian J.; Howard, Melissa; Jelčić, Ilijas; Kaskow, Belinda J.; Kira, Jun Ichi; Kleinová, Pavlína; Kockum, Ingrid; Kucerova, Karolina; Lill, Christina M.; Luessi, Felix; Malhotra, Sunny; Martin, Roland; Martinelli, Filippo; Matsushita, Takuya; McCabe, Cristin; McCauley, Jacob L.; Mescheriakkova, Julia; Mitrovič, Mitja; Moen, Stine Marit; Montalbán, Xavier; Mühlau, Mark; Nakmura, Yuri; Oksenberg, Jorge R.; Olsson, Tomas; Oturai, Annette Bang; Palotie, Aarno; Patsopoulos, Nikolaos A.; Pavlicova, Jana; Pericak-Vance, Peggy; Piehl, Fredrik; Rebeix, I.; Rioux, John D.; Saarela, Janna; Sawcer, Stephen; Sellebjerg, Finn; Søndergaard, Helle Bach; Sørensen, Per Soelberg; Sospedra, Mireia; Spurkland, Anne; Stewart, Graeme J.; Taylor, Bruce; Uitterlinden, André G.; Duijn, Cornelia M. van; Zipp, Frauke

doi:10.1016/j.neuron.2016.09.052

Cited by 21 publications

(12 citation statements)

References 15 publications

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“…One of these examples is a variant of a gene involved in transcriptional regulation (NR1H3), which was only found to be associated with PPMS, but not with other disease forms (25). This observation, however, also highlights a caveat regarding the interpretation of such data, since it has not been confirmed in a detailed analysis of the much larger dataset (26). Overall, however, these data indicate that there is a basic polygenic pattern determining the global MS risk and this is the same for all disease courses and involves immune mediated mechanisms (27), while the development of progressive disease may be additionally fostered by genetic variants associated with lipid metabolism or neurodegeneration.…”

Section: Geneticsmentioning

confidence: 82%

Pathogenic Mechanisms Associated With Different Clinical Courses of Multiple Sclerosis

2019

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In the majority of patients multiple sclerosis starts with a relapsing remitting course (RRMS), which may at later times transform into secondary progressive disease (SPMS). In a minority of patients the relapsing remitting disease is skipped and the patients show progression from the onset (primary progressive MS, PPMS). Evidence obtained so far indicate major differences between RRMS and progressive MS, but no essential differences between SPMS and PPMS, with the exception of a lower incidence in the global load of focal white matter lesions and in particular in the presence of classical active plaques in PPMS. We suggest that in MS patients two types of inflammation occur, which develop in parallel but partially independent from each other. The first is the focal bulk invasion of T- and B-lymphocytes with profound blood brain barrier leakage, which predominately affects the white matter, and which gives rise to classical active demyelinated plaques. The other type of inflammation is a slow accumulation of T-cells and B-cells in the absence of major blood brain barrier damage in the connective tissue spaces of the brain, such as the meninges and the large perivascular Virchow Robin spaces, where they may form aggregates or in most severe cases structures in part resembling tertiary lymph follicles. This type of inflammation is associated with the formation of subpial demyelinated lesions in the cerebral and cerebellar cortex, with slow expansion of pre-existing lesions in the white matter and with diffuse neurodegeneration in the normal appearing white or gray matter. The first type of inflammation dominates in acute and relapsing MS. The second type of inflammation is already present in early stages of MS, but gradually increases with disease duration and patient age. It is suggested that CD8+ T-lymphocytes remain in the brain and spinal cord as tissue resident cells, which may focally propagate neuroinflammation, when they re-encounter their cognate antigen. B-lymphocytes may propagate demyelination and neurodegeneration, most likely by producing soluble neurotoxic factors. Whether lymphocytes within the brain tissue of MS lesions have also regulatory functions is presently unknown. Key open questions in MS research are the identification of the target antigen recognized by tissue resident CD8+ T-cells and B-cells and the molecular nature of the soluble inflammatory mediators, which may trigger tissue damage.

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Section: Geneticsmentioning

confidence: 82%

Pathogenic Mechanisms Associated With Different Clinical Courses of Multiple Sclerosis

2019

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“…The frequent observation of familial clustering in MS, together with a seemingly Mendelian inheritance pattern in some families, has led to the expectation that highly penetrant variants in recurrent disease genes might also be responsible for at least some cases. Disappointingly, though hundreds of multi-case families were analyzed through linkage analyses and next-generation sequencing over the last two decades, not a single unequivocally accepted locus or disease gene was identified [ 13 , 14 , 19 , 20 ]. Although several promising genes were nominated, none of them could be replicated in subsequent studies [ 13 , 14 , 21 ].…”

Section: Discussionmentioning

confidence: 99%

“…Disappointingly, though hundreds of multi-case families were analyzed through linkage analyses and next-generation sequencing over the last two decades, not a single unequivocally accepted locus or disease gene was identified [ 13 , 14 , 19 , 20 ]. Although several promising genes were nominated, none of them could be replicated in subsequent studies [ 13 , 14 , 21 ]. These observations led part of the MS genetics community to doubt the existence of high-penetrant disease genes at all [ 3 , 20 ].…”

Section: Discussionmentioning

confidence: 99%

“…In the last decade, a number of putative familial high-risk genes were suggested by whole-exome sequencing (WES) studies of multi-case MS families [ 10 , 11 , 12 ]. However, none of these genes were confirmed in independent studies [ 10 , 11 , 12 , 13 , 14 , 15 ]. To elucidate potential putative high-risk genes, we performed WES in four MS families with three or more affected individuals and filtered for rare variants segregating with disease in the respective family.…”

Section: Introductionmentioning

confidence: 97%

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Exome-Sequence Analyses of Four Multi-Incident Multiple Sclerosis Families

Zrzavy

Leutmezer

Kristoferitsch

et al. 2020

Genes

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Multiple sclerosis (MS) is an inflammatory demyelinating disease of the Central Nervous System (CNS). Currently, it is estimated that 30–40% of the phenotypic variability of MS can be explained by genetic factors. However, low susceptibility variants identified through Genome Wide Association Study (GWAS) were calculated to explain about 50% of the heritability. Whether familial high-risk variants also contribute to heritability is a subject of controversy. In the last few years, several familial variants have been nominated, but none of them have been unequivocally confirmed. One reason for this may be that genetic heterogeneity and reduced penetrance are hindering detection. Sequencing a large number of MS families is needed to answer this question. In this study, we performed whole exome sequencing in four multi-case families, of which at least three affected individuals per family were analyzed. We identified a total of 138 rare variants segregating with disease in each of the families. Although no single variant showed convincing evidence for disease causation, some genes seemed particularly interesting based on their biological function. The main aim of this study was to provide a complete list of all rare segregating variants to provide the possibility for other researchers to cross-check familial candidate genes in an unbiased manner.

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“…A major goal is to resolve the question: how much of the pathobiology of MS can be recapitulated by a primary metabolic defect in oligodendrocytes? Answering this question may yield insights into whether adaptive immune activation and CNS invasion are etiologic for MS or, rather, reflect inside-out processes with heightened susceptibility to inflammation that is dependent on immune haplotype or other genetic/environmental modifiers 28 , 29 .…”

Section: Introductionmentioning

confidence: 99%

Corticohippocampal Dysfunction In The OBiden Mouse Model Of Primary Oligodendrogliopathy

Radecki

Johnson

Brown

et al. 2018

Sci Rep

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Despite concerted efforts over decades, the etiology of multiple sclerosis (MS) remains unclear. Autoimmunity, environmental-challenges, molecular mimicry and viral hypotheses have proven equivocal because early-stage disease is typically presymptomatic. Indeed, most animal models of MS also lack defined etiologies. We have developed a novel adult-onset oligodendrogliopathy using a delineated metabolic stress etiology in myelinating cells, and our central question is, “how much of the pathobiology of MS can be recapitulated in this model?” The analyses described herein demonstrate that innate immune activation, glial scarring, cortical and hippocampal damage with accompanying electrophysiological, behavioral and memory deficits naturally emerge from disease progression. Molecular analyses reveal neurofilament changes in normal-appearing gray matter that parallel those in cortical samples from MS patients with progressive disease. Finally, axon initial segments of deep layer pyramidal neurons are perturbed in entorhinal/frontal cortex and hippocampus from OBiden mice, and computational modeling provides insight into vulnerabilities of action potential generation during demyelination and early remyelination. We integrate these findings into a working model of corticohippocampal circuit dysfunction to predict how myelin damage might eventually lead to cognitive decline.

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NR1H3 p.Arg415Gln Is Not Associated to Multiple Sclerosis Risk

Cited by 21 publications

References 15 publications

Pathogenic Mechanisms Associated With Different Clinical Courses of Multiple Sclerosis

Pathogenic Mechanisms Associated With Different Clinical Courses of Multiple Sclerosis

Exome-Sequence Analyses of Four Multi-Incident Multiple Sclerosis Families

Corticohippocampal Dysfunction In The OBiden Mouse Model Of Primary Oligodendrogliopathy

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