Association of NOD2 and IFNG single nucleotide polymorphisms with leprosy in the Amazon ethnic admixed population

Leturiondo, André Luiz; Noronha, Ariani Batista; Mendonça, Carla Yael Ribeiro; Ferreira, Cynthia de Oliveira; Alvarado-Arnez, Lucia Elena; Manta, Fernanda Saloum de Neves; Bezerra, Ohanna Cavalcanti de Lima; Carvalho, E.F.; Moraes, Milton Ozório; Rodrigues, Fabíola da Costa; Talhari, Carolina

doi:10.1371/journal.pntd.0008247

Cited by 18 publications

(23 citation statements)

References 55 publications

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“…NUDT22 is a Mg 2+ -dependent UDP-glucose and UDP-galactose hydrolase( 64 ), while high glucose shows a negative effect in HIE like stroke( 65 ). CCDC122 potentially pro-inflammatory( 66 ).…”

Section: Resultsmentioning

confidence: 99%

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A chronopharmacology-friendly multi-target therapeutics based on AI: the example of therapeutic hypothermia

Liu

Jiang

Zhang

2022

Preprint

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Background Computer-aided drug discovery (CADD) is a widely used method for drug discovery with many successes. Meanwhile, CADD has the limitation of analyzing multi-level scores such as docking results of multiple proteins with multiple drugs. Results We propose a method of PageRank to solve the problem. This method can make a comprehensive ranking based on multi-level scores. Then we take an example of therapeutic hypothermia (TH). Three levels of TH data were used in the article: the log2 foldchange (logFC) of proteins, the relative expression values of mRNA, and the docking scores of proteins and molecules. After calculation, we get the comprehensive drug rank and drug combination rank of each group of TH, which means we can generate the rank of drug directly from bioinformatics. Based on this method, we raised the concept of bioinfo-pharmacology. Conclusions Given the high rationality and compatibility of bioinfo-pharmacology, it can effectively enhance popular drug discovery techniques such as the docking or pharmacophore model. Besides, it could advance the application of precision medicine.

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Section: Resultsmentioning

confidence: 99%

“…NUDT22 is an Mg 2+ -dependent UDP-glucose and UDP-galactose hydrolase[44], while high glucose shows a negative effect in HIE like stroke[45]. CCDC122 potentially pro-inflammatory[46]. CIRP can effectively reduce cell death in the early stage of hypothermia therapy.…”

Section: Resultsmentioning

confidence: 99%

A chronopharmacology-friendly multi-target therapeutics based on AI: the example of therapeutic hypothermia

Liu

Jiang

Zhang

2022

Preprint

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“…By applying unbiased WGS analysis on a family with monozygotic twins with extreme early-onset leprosy, we identified three coding variants in the LRRK2 and NOD2 genes as strong candidates for contributing to early-onset leprosy susceptibility. Rare and common variants in both genes had previously been associated with leprosy and leprosy reactions by candidate and genome-wide association studies (3,6,7,(24)(25)(26)(27)(28)(29)(30). Intriguingly, the same coding variants identified in the leprosy family have been implicated in reduced susceptibility to PD and CD (8).…”

Section: Discussionmentioning

confidence: 98%

Early onset leprosy reveals a joint effect of LRRK2 and NOD2 variants

Dallmann-Sauer

Yong

Costa

et al. 2021

Preprint

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Leprosy, caused by Mycobacterium leprae, has a long incubation period and cases with age-of-onset <5 years are rare. Here, we studied a three-generational multiplex leprosy family which included monozygotic twins age <24 months suffering from paucibacillary leprosy. Whole genome sequencing identified a homozygous double mutation in the LRRK2 gene (N551K, R1398H) and a heterozygous mutation in NOD2 (R702W) as candidate variants underlying the early onset phenotype in the twins. The same amino acid substitutions had previously been identified as shared risk-modulating factors for Crohn's disease and Parkinson's disease. To evaluate the functional impact of the LRRK2 mutations, we employed genome editing in RAW264.7 cells. Cells expressing the LRRK2 variants displayed reduced respiratory burst and apoptosis following mycobacterial challenge. Moreover, the BCG-induced respiratory burst was significantly lower in LRRK2 wild-type-expressing cells transfected with NOD2 R702W compared with NOD2 wild-type constructs. Employing co-immunoprecipitation, we showed that LRRK2 and NOD2 wild-type proteins interact in RAW cells. This interaction was independent of the LRRK2 variants but strongly reduced for NOD2 R702W. However, N-glycolyl MDP-triggered RIP2 phosphorylation and NF-kB activation were additively reduced by both LRRK2 and NOD2 mutations. Finally, we observed a joint effect of LRRK2 and NOD2 variants on cytokine/chemokine secretion with the most significant reduction of secretion observed for the mutant genotypes carried by the twins. These data demonstrated the pleiotropic effects of LRRK2 and NOD2 in response to mycobacterial infection consistent with a role of the identified mutations in the development of early onset leprosy.

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“…S1P pathway and TRAIL signaling pathway have been extensively investigated as potential targets for treatments of multiple diseases. It has been reported that the bi-directional promoter region of PACRG and Parkin genes is associated with susceptibility to leprosy and several types of cancer, but the underlying mechanisms are still poorly elucidated [ 10 , 13 , 32 , 33 , 34 , 35 , 36 ]. Leprosy is a chronic infectious disease caused by Mycobacterium leprae , and clinical manifestations of leprosy are strongly correlated with the host’s immune responses [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Functional Expression, Purification and Identification of Interaction Partners of PACRG

et al. 2021

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PACRG (Parkin co-regulated gene) shares a bi-directional promoter with the Parkinson’s disease-associated gene Parkin, but the physiological roles of PACRG have not yet been fully elucidated. Recombinant expression methods are indispensable for protein structural and functional studies. In this study, the coding region of PACRG was cloned to a conventional vector pQE80L, as well as two cold-shock vectors pCold II and pCold-GST, respectively. The constructs were transformed into Escherichia coli (DE3), and the target proteins were overexpressed. The results showed that the cold-shock vectors are more suitable for PACRG expression. The soluble recombinant proteins were purified with Ni2+ chelating column, glutathione S-transferase (GST) affinity chromatography and gel filtration. His6 pull down assay and LC-MS/MS were carried out for identification of PACRG-binding proteins in HEK293T cell lysates, and a total number of 74 proteins were identified as potential interaction partners of PACRG. GO (Gene ontology) enrichment analysis (FunRich) of the 74 proteins revealed multiple molecular functions and biological processes. The highest proportion of the 74 proteins functioned as transcription regulator and transcription factor activity, suggesting that PACRG may play important roles in regulation of gene transcription.

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Association of NOD2 and IFNG single nucleotide polymorphisms with leprosy in the Amazon ethnic admixed population

Cited by 18 publications

References 55 publications

A chronopharmacology-friendly multi-target therapeutics based on AI: the example of therapeutic hypothermia

A chronopharmacology-friendly multi-target therapeutics based on AI: the example of therapeutic hypothermia

Early onset leprosy reveals a joint effect of LRRK2 and NOD2 variants

Functional Expression, Purification and Identification of Interaction Partners of PACRG

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