Molecular mechanism for the multiple sclerosis risk variant rs17594362

Abstract Multiple sclerosis (MS) is known as an autoimmune demyelinating disease of the central nervous system. However, its cause remains elusive. Given previous studies suggesting that dysfunctional oligodendrocytes (OLs) may trigger MS, we tested whether single nucleotide polymorphisms (SNPs) associated with MS affect OL enhancers, potentially increasing MS risk by dysregulating gene expression of OL lineage cells. We found that two closely spaced OL enhancers, which are 3 Kb apart on chromosome 13, overlap two MS SNPs in linkage disequilibrium—rs17594362 and rs12429256. Our data revealed that the two MS SNPs significantly up-regulate the associated OL enhancers, which we have named as Rgcc-E1 and Rgcc-E2. Analysis of Hi-C data and epigenome editing experiments shows that Rgcc is the primary target of Rgcc-E1 and Rgcc-E2. Collectively, these data indicate that the molecular mechanism of rs17594362 and rs12429256 is to induce Rgcc overexpression by potentiating the enhancer activity of Rgcc-E1 and Rgcc-E2. Importantly, the dosage of the rs17594362/rs12429256 risk allele is positively correlated with the expression level of Rgcc in the human population, confirming our molecular mechanism. Our study also suggests that Rgcc overexpression in OL lineage cells may be a key cellular mechanism of rs17594362 and rs12429256 for MS.

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Upregulation of c-MYC in cis through a Large Chromatin Loop Linked to a Cancer Risk-Associated Single-Nucleotide Polymorphism in Colorectal Cancer Cells

Molecular and Cellular Biology ◽

10.1128/mcb.01384-09 ◽

2010 ◽

Vol 30 (6) ◽

pp. 1411-1420 ◽

Cited By ~ 177

Author(s):

Jason B. Wright ◽

Seth J. Brown ◽

Michael D. Cole

Keyword(s):

Cancer Risk ◽

Cancer Cells ◽

Association Studies ◽

Beta Catenin ◽

Genome Wide Association Studies ◽

Chromatin Loop ◽

Nucleotide Polymorphisms ◽

Distal Enhancer ◽

Enhancer Activity ◽

Single Nucleotide

ABSTRACT Genome-wide association studies have mapped many single-nucleotide polymorphisms (SNPs) that are linked to cancer risk, but the mechanism by which most SNPs promote cancer remains undefined. The rs6983267 SNP at 8q24 has been associated with many cancers, yet the SNP falls 335 kb from the nearest gene, c-MYC. We show that the beta-catenin-TCF4 transcription factor complex binds preferentially to the cancer risk-associated rs6983267(G) allele in colon cancer cells. We also show that the rs6983267 SNP has enhancer-related histone marks and can form a 335-kb chromatin loop to interact with the c-MYC promoter. Finally, we show that the SNP has no effect on the efficiency of chromatin looping to the c-MYC promoter but that the cancer risk-associated SNP enhances the expression of the linked c-MYC allele. Thus, cancer risk is a direct consequence of elevated c-MYC expression from increased distal enhancer activity and not from reorganization/creation of the large chromatin loop. The findings of these studies support a mechanism for intergenic SNPs that can promote cancer through the regulation of distal genes by utilizing preexisting large chromatin loops.

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HIV infection and multiple sclerosis: a case with unexpected “no evidence of disease activity” status

Journal of International Medical Research ◽

10.1177/0300060521999577 ◽

2021 ◽

Vol 49 (3) ◽

pp. 030006052199957

Author(s):

Fernando Labella ◽

Fernando Acebrón ◽

María del Carmen Blanco-Valero ◽

Alba Rodrígez-Martín ◽

Ángela Monterde Ortega ◽

...

Keyword(s):

Multiple Sclerosis ◽

Hiv Infection ◽

Disease Activity ◽

Demyelinating Disease ◽

Clinical Course ◽

Disease Modifying Drugs ◽

Immunodeficiency Virus ◽

Relapsing Remitting ◽

The Central Nervous System ◽

Disease Modifying

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system whose etiology remains unclear. It has been suggested that MS can be triggered by certain viruses; however, human immunodeficiency virus (HIV) infection is associated with reduced incidence of MS. We present the case of a young patient diagnosed with active relapsing-remitting MS whose clinical course substantially improved following HIV infection and treatment. The patient achieved no evidence of disease activity status without any disease-modifying drugs. Both HIV-induced immunosuppression and antiretroviral therapy may have attenuated the clinical course in this patient.

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Recent advances on immunosuppressive drugs and remyelination enhancers for the treatment of multiple sclerosis

Current Pharmaceutical Design ◽

10.2174/1381612827666210127121829 ◽

2021 ◽

Vol 27 ◽

Author(s):

Jennifer Cadenas-Fernández ◽

Pablo Ahumada-Pascual ◽

Luis Sanz Andreu ◽

Ana Velasco

Keyword(s):

Multiple Sclerosis ◽

Intracellular Signaling ◽

Demyelinating Disease ◽

Lipid Synthesis ◽

Immunosuppressive Drugs ◽

Nerve Fibers ◽

Myelin Sheaths ◽

Demyelinating Lesions ◽

The Central Nervous System ◽

Lipid Structures

: Mammalian nervous systems depend crucially on myelin sheaths covering the axons. In the central nervous system, myelin sheaths consist of lipid structures which are generated from the membrane of oligodendrocytes (OL). These sheaths allow fast nerve transmission, protect axons and provide them metabolic support. In response to specific traumas or pathologies, these lipid structures can be destabilized and generate demyelinating lesions. Multiple sclerosis (MS) is an example of a demyelinating disease in which the myelin sheaths surrounding the nerve fibers of the brain and spinal cord are damaged. MS is the leading cause of neurological disability in young adults in many countries, and its incidence has been increasing in recent decades. Related to its etiology, it is known that MS is an autoimmune and inflammatory CNS disease. However, there are no effective treatments for this disease and the immunomodulatory therapies that currently exist have proven limited success since they only delay the progress of the disease. Nowadays, one of the main goals in the MS research is to find treatments which allows the recovery of neurological disabilities due to demyelination. To this end, different approaches, such as modulating intracellular signaling or regulating the lipid metabolism of OLs, are being considered. Here, in addition to immunosuppressive or immunomodulatory drugs that reduce the immune response against myelin sheaths, we review a diverse group of drugs that promotes endogenous remyelination in MS patients and whose use may be interesting as potential therapeutic agents in MS disease. To this end, we compile specific treatments against MS that are currently in the market with remyelination strategies which have entered into human clinical trials for future reparative MS therapies. The method used in this study is a systematic literature review on PubMed, Web of Science and Science Direct databases up to May 31, 2020. To narrow down the search results in databases, more specific keywords, such as, “myelin sheath”, “remyelination”, “demyelination”, “oligodendrocyte” and “lipid synthesis” were used to focus the search. We favoured papers published after January, 2015, but did not exclude earlier seminal papers.

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Relapsing Tumefactive Demyelination: A Case Report

Acta Medica Academica ◽

10.5644/ama2006-124.231 ◽

2018 ◽

Vol 47 (2) ◽

pp. 193

Author(s):

Ibrahim Omerhodžić ◽

Almir Džurlić ◽

Dino Lisica ◽

Nevena Mahmutbegović ◽

Maida Nikšić ◽

...

Keyword(s):

Multiple Sclerosis ◽

Case Report ◽

Female Patient ◽

Demyelinating Disease ◽

Diagnostic Procedures ◽

Young Female ◽

Diagnostic Challenge ◽

Fresh Frozen ◽

The Central Nervous System ◽

Tumorlike Lesion

Objective. We present a case of relapsing tumefactive demyelination in a young female patient, that posed a real diagnostic challenge, with a heterogeneous clinical picture, atypical for multiple sclerosis (MS) presentation, and neuroradiological manifestations with a high suspicion of neoplastic diseases.Case Report. An 18-year old female patient presented to our Neurosurgical Out-patients’ Clinic with symptoms atypical for multiple sclerosis, unremarkable neurological deficit, one tumefactive lesion on MRI, followed by relapse and another two lesions within a period of six months. We decided to perform biopsy of the tumefactive lesion with compressive effect. Serological and clinical data were negative for MS, and the patient did not respond well to corticosteroid therapy. Fresh frozen tumor tissue aroused a strong suspicion of gemistocytic astrocytoma, so total resection was done, but the definitive pathohistological examination confirmed tumefactive demyelination.Conclusion. For clinicians, it is important to consider demyelinating disease in the differential diagnosis of a tumorlike lesion of the central nervous system, in order to avoid invasive and potentially harmful diagnostic procedures, especially in younger patients.

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Multiple Sclerosis

Neuropathic Pain ◽

10.1093/med/9780190298357.003.0024 ◽

2018 ◽

pp. 209-216

Author(s):

Samuel W. Samuel ◽

Jianguo Cheng

Keyword(s):

Multiple Sclerosis ◽

Central Nervous System ◽

Neuropathic Pain ◽

Demyelinating Disease ◽

Spontaneous Pain ◽

Disease Course ◽

The Central Nervous System ◽

Disease Modifying ◽

Multiple Treatments ◽

Surgical Treatments

Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system (CNS). The diagnosis is based on evidence of at lease two different lesions in the CNS, at least two different episodes in the disease course, and chronic inflammation of the CNS as determined by analysis of the cerebrospinal fluid. Central neuropathic pain is the most common form of pain in patients with MS, with an estimated prevalence of about 50%. Along with the classical neuropathic pain features, such as spontaneous pain (dysesthesia and burning) and evoked pain (allodynia and hyperalgesia), patients with MS may also suffer from intermittent neuropathic pain, such as trigeminal neuralgia, Lhermitte sign, and glossopharyngeal neuralgia. In addition to disease-modifying therapies of MS, multiple treatments are available to manage neuropathic pain secondary to MS, including medical, interventional, and surgical treatments with varying levels of evidence.

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

Genes ◽

10.3390/genes11090988 ◽

2020 ◽

Vol 11 (9) ◽

pp. 988

Author(s):

Tobias Zrzavy ◽

Fritz Leutmezer ◽

Wolfgang Kristoferitsch ◽

Barbara Kornek ◽

Christine Schneider ◽

...

Keyword(s):

Multiple Sclerosis ◽

Genome Wide Association Study ◽

Rare Variants ◽

Demyelinating Disease ◽

Phenotypic Variability ◽

Convincing Evidence ◽

Risk Variants ◽

Unbiased Manner ◽

The Central Nervous System ◽

Reduced Penetrance

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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