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Beckwith–Wiedemann Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Jirat Chenbhanich, Sirisak Chanprasert, Wisit Cheungpasitporn
Until recently, there has been increasing evidence of trans-acting mechanism as a cause of secondary DNA methylation defect; in fact, it accounts for approximately 25% of BWS patients with ICR2 hypomethylation and includes multilocus imprinting disorder and NLRP2 mutation [8]. Approximately 24% of BWS patients with ICR2 hypomethylation displayed a loss of methylation at multiple loci across the genome [28]—a condition called multilocus imprinting disorder. In multilocus imprinting disorder with BWS phenotype, the commonly affected loci include ICR2, GNAS, IGF2R, and PEG1 [8]. Furthermore, a homozygous NLRP2 mutation was found in a mother of two children with BWS and ICR2 hypomethylation, with one of the children demonstrating multilocus imprinting defect with partial loss of methylation at PEG1 locus [29]. NLRP2 is located on chromosome 19q13.4; this finding suggested that NLRP2 has a role in establishing and maintaining genomic imprinting in humans.
Epigenetic and Assisted Reproduction Epidemiological Studies
Published in Cristina Camprubí, Joan Blanco, Epigenetics and Assisted Reproduction, 2018
The molecular basis for MLID is currently unknown. The observation that different DMRs are affected in MLID but without an obvious pattern of loci indicates that the steps of the imprinting cycle of life (establishment, maintenance or erasure of imprinting markers) are disturbed, but the resulting aberrant methylation show a random distribution. Two causes for MLID are currently discussed. There are an increasing number of reports indicating that genomic mutations play a major in the etiology of MLID. In TNDM and in some SRS and BWS families, genomic mutations in ZFP57 or NLRP genes (NLRP2, 5, 7) have meanwhile been identified to be associated with MLID (7,10–12). Additionally, in recent studies on BWS and SRS patients born after assisted reproduction, the frequency of MLID among the 11p15 epimutation carriers has been determined. In fact, a higher number of MLID carriers could be identified in the ART conceived patients than in the general ImpDis cohorts (e.g., 21.2% in BWS patients conceived by ART vs. 4.5% in the general ICR2 LOM cohort (13). However, the number of patients is low and the ascertainment is biased and not standardized. Nevertheless, studies from other mammals indicate an increased incidence of misregulation of multiple imprinted genes in ART cohorts when compared with controls (14). Thus, it can be hypothesized that some steps of the ART procedure predispose to the disturbance of the fine-tuned methylation marking of DMRs. However, the frequency of ART conceived children in the BWS cohorts (Table 7.2) indicates that the 11p15 imprinted loci are particularly prone to these external influences.
Major depressive disorder (mdd): emerging immune targets at preclinical level
Published in Expert Opinion on Therapeutic Targets, 2023
Manasi Varma, Arshpreet Kaur, Ranjana Bhandari, Ashwani Kumar, Anurag Kuhad
While some other NLRs like NLRP1 and NLRP2 have also been identified in the CNS, NLRP3, which is largely expressed in the microglia, has been subjected to the greatest degree of investigations, owing to its role in the activation of caspase−1 and subsequent stimulation of multiple inflammatory pathways [118–120]. Upon activation, the assembly of the NLRP3 inflammasome begins, along with the recruitment of pro-caspase−1 and apoptosis-associated speck-like protein (ASC), an important adaptor protein which functions as a mediator of their functions [121]. Apart from activating the caspase system, NLRP3 is also responsible for causing the proteolytic cleavage of IL−1β and pro-IL−18 [122], both of which are involved in autophagy and cellular damage. IL−1α, IL−33, IL−1F7β are also stimulated [123–125]. These pathways are known to be responsible for ROS production, which in turn is important in the propagation of neuro-inflammation.
A new NLRP5 mutation causes female infertility and total fertilization failure
Published in Gynecological Endocrinology, 2021
Mingzhao Li, Miaomiao Jia, Xiaoli Zhao, Rong Shi, Xia Xue
NLRP5 is a maternal effect gene, and the encoded protein is a member of the subcortical maternal complex (SCMC) which is essential for embryogenesis. Early embryonic arrest is one of the major causes of recurrent ART failure, yet its genetic determinant is still largely unknown as only a few mutations in genes encoding SCMC have been reported to result in this phenotype. Two studies recently demonstrated that NLRP5 mutations were responsible for human early embryonic arrest [9,10]. Mu et al. confirmed that NLRP2 and NLRP5 were novel mutant genes responsible for human early embryonic arrest [9]. Xu et al. described a female in a consanguineous Chinese family who displayed clinical features of early embryonic arrest and identified a novel homozygous variant c.1061C > T (p.Pro354Leu) in NLRP5 [10].
Influence of the inflammasome complex on psychiatric disorders: clinical and preclinical studies
Published in Expert Opinion on Therapeutic Targets, 2021
Although BD is known to be hereditary (about 60 ~ 80%), immune disturbance could be a pathologic factor involved in its pathophysiology [85,86]. An inflammatory response is observed in BD patients; higher levels of pro-inflammatory cytokines and lower levels of anti-inflammatory cytokines are found during manic and depressive phases of BD [92]. As mentioned above, most BD patients experience depressive episode, even though they have BD-1 [85]. Their pathophysiology may overlap. In clinical studies, aberrant activation of peripheral inflammatory response and elevation of cytokine levels are observed in during abnormal mood states in BD [93]. Inflammatory cytokines, including IL-1β, IL-6, IL-18, IL-1ra, IFN-γ, and TNF-α, are elevated in BD, compared to control [93]. BD subjects in abnormal mood states (both mania and depression) exhibit increased inflammasome-associated cytokine IL-1β and IL-18 levels, compared to the euthymic state [93]. During manic episodes, elevated levels of pro-inflammatory cytokines, including IL-2, IL-4, and IL-6 are observed in the sera of patients with BD; however, during depressive episodes, increased IL-6 level is detected in their sera [94]. Enhanced pro-inflammatory IL-1β level is found in the CSF of patients with BD [95]. In a meta-analysis, alterations in the levels of cytokines, e.g. IL-1β and TNF-α, were reported to be closely associated with BD [96]. Additionally, adolescents with BD display higher levels of circulating pro-inflammatory cytokine IL-1β in the plasma, compared to healthy controls [97]. Higher levels of the activated form of NF-κB were detected in the PBMCs, monocytes, and lymphocytes isolated from adolescents with BD than in those isolated from healthy controls [97]. Plasma from patients with BD in manic and hypomanic states contained increased levels of pro-inflammatory IL-6 and IL-18, compared to those in euthymic and depressive states or healthy controls [98]. BD patients have higher levels of pro-inflammatory monocytes and inflammatory cytokines, such as C–C Motif Chemokine Ligand 2 (CCL2) and pentraxin 3 (PTX3) in their sera [99]. Simultaneously, BD patients exhibit upregulation of anti-inflammatory T lymphocytes. However, BD patients, known to be susceptible to autoimmune diseases, are found to be deficient in these T lymphocytes [99,100]. Monocytes from BD patients exhibit aberrant mRNA expression of inflammatory genes, including IL1B, TNF, IL6, PTX3, CCL2, CCL7, CCL20, CXCL2, and CCR2 [101]. Importantly, patients with BD exhibit activated NLRP3 inflammasome due to increased gene expressions of NLRP3, ASC, and caspase-1, and further upregulated levels of IL-1β and IL-18 in PBMCs [102]. Postmortem frontal cortex demonstrated significant upregulation of mitochondrial NLRP3, ASC, and caspase-1, as well as pro-inflammatory IL-1β, IL-18, and TNF-α in patients with BD [103]. Furthermore, neural stem cells from BD patients show increased expression levels of the NLRP2 gene [104]. During progression of BD, NLRP2 gene expression was found to be elevated in induced pluripotent stem cells and cortical neural stem cells from BD patients, as compared to healthy controls [105].