The mtDNA replication-related genes TFAM and POLG are associated with leprosy in Han Chinese from Southwest China

Wang, Dong; Li, Guodong; Yu, Fan; Df, Zhang; Bi, Rui; Yu, Xiaofeng; Long, Haixia; Li, Yuye; Yao, Yong‐Gang

doi:10.1016/j.jdermsci.2017.09.001

Cited by 10 publications

(6 citation statements)

References 65 publications

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“…Further studies will be needed to map the functional variants in this region. 22,23,30,55 This pattern supports the notion that genetic variants might be associated with leprosy polarization. 56 Further survival analysis showed that rs142179458-A is associated with earlier age of MB onset (Gehan-Breslow-Wilcoxon test p ¼ 0.025; Figure S6).…”

Section: Validation Of Leprosy-associated Missense Variants By Targeted Ngssupporting

confidence: 79%

“…In the replication cohort (sample III), we used the previously reported case and control cohort (527 individuals with leprosy and 583 healthy subjects) from the Yuxi Prefecture, Yunnan Province. 22,23,[29][30][31] All individuals with leprosy were diagnosed by clinical and histopathological features and/or bacteriological index (if available), as had been described in our previous epidemiological study. 32 The regionally matched healthy individuals had no history of leprosy, HIV infection, or tuberculosis.…”

Section: Subjectsmentioning

confidence: 99%

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Missense Variants in HIF1A and LACC1 Contribute to Leprosy Risk in Han Chinese

Wang

Malhi

et al. 2018

The American Journal of Human Genetics

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Genome-wide association studies (GWASs) and genome-wide linkage studies (GWLSs) have identified numerous risk genes affecting the susceptibility to leprosy. However, most of the reported GWAS hits are noncoding variants and account for only part of the estimated heritability for this disease. In order to identify additional risk genes and map the potentially functional variants within the GWAS loci, we performed a three-stage study combining whole-exome sequencing (WES; discovery stage), targeted next-generation sequencing (NGS; screening stage), and refined validation of risk missense variants in 1,433 individuals with leprosy and 1,625 healthy control individuals from Yunnan Province, Southwest China. We identified and validated a rare damaging variant, rs142179458 (c.1045G>A [p.Asp349Asn]) in HIF1A, as contributing to leprosy risk (p = 4.95 × 10, odds ratio [OR] = 2.266). We were able to show that affected individuals harboring the risk allele presented with multibacillary leprosy at an earlier age (p = 0.025). We also confirmed the association between missense variant rs3764147 (c.760A>G [p.Ile254Val]) in the GWAS hit LACC1 (formerly C13orf31) and leprosy (p = 6.11 × 10, OR = 1.605). By using the population attributable fraction, we have shown that HIF1A and LACC1 are the major genes with missense variants contributing to leprosy risk in our study groups. Consistently, mRNA expression levels of both HIF1A and LACC1 were upregulated in the skin lesions of individuals with leprosy and in Mycobacterium leprae-stimulated cells, indicating an active role of HIF1A and LACC1 in leprosy pathogenesis.

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Section: Validation Of Leprosy-associated Missense Variants By Targeted Ngssupporting

confidence: 79%

Section: Subjectsmentioning

confidence: 99%

Missense Variants in HIF1A and LACC1 Contribute to Leprosy Risk in Han Chinese

Wang

Malhi

et al. 2018

The American Journal of Human Genetics

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“…For example, rare variants −91 C A in 5′-UTR exon 1 and the Ala105Thr missense mutation of TFAM were shown to be involved in the pathogenesis of cardiac hypertrophy [ 306 ] and variants rs10826175 (A G) SNP upstream and rs1937 (G C) SNP in exon 1 of TFAM were associated with diffuse-type gastric cancer [ 274 ]. Genetic variants of TFAM (SNPs rs1049432; rs1937) can have an active role in host response to Mycobacterium leprae, causing leprosy, and affect the risk of infection [ 135 , 307 ]. Pro-178 within HMG-box 2 is an important residue for intercalating into the DNA minor groove and creating contacts between TFAM and mtDNA [ 208 ].…”

Section: Involvement Of Tfam In Cellular Pathologiesmentioning

confidence: 99%

Mitochondrial HMG-Box Containing Proteins: From Biochemical Properties to the Roles in Human Diseases

et al. 2020

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Mitochondrial DNA (mtDNA) molecules are packaged into compact nucleo-protein structures called mitochondrial nucleoids (mt-nucleoids). Their compaction is mediated in part by high-mobility group (HMG)-box containing proteins (mtHMG proteins), whose additional roles include the protection of mtDNA against damage, the regulation of gene expression and the segregation of mtDNA into daughter organelles. The molecular mechanisms underlying these functions have been identified through extensive biochemical, genetic, and structural studies, particularly on yeast (Abf2) and mammalian mitochondrial transcription factor A (TFAM) mtHMG proteins. The aim of this paper is to provide a comprehensive overview of the biochemical properties of mtHMG proteins, the structural basis of their interaction with DNA, their roles in various mtDNA transactions, and the evolutionary trajectories leading to their rapid diversification. We also describe how defects in the maintenance of mtDNA in cells with dysfunctional mtHMG proteins lead to different pathologies at the cellular and organismal level.

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“…However, we still know very little about how mitochondrial perturbations drive protective or pathogenic immune responses in the context of actual human disease. Human mutations in genes associated with mitochondrial function have been linked to chronic inflammation [14][15][16][17][18][19] and susceptibility to infection with pathogens like Mycobacterium leprae and Mycobacterium tuberculosis (Mtb) [20][21][22][23][24] , which cause the chronic infections leprosy and tuberculosis, respectively. For example, mitophagy genes (e.g.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial dysfunction promotes alternative gasdermin D-mediated inflammatory cell death and susceptibility to infection

Weindel

Zhao

Martinez

et al. 2021

Preprint

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SUMMARYHuman mutations in mitochondrial-associated genes are associated with inflammatory diseases and susceptibility to infection. However, their mechanistic contributions to immune outcomes remain ill-defined. We discovered that the disease-associated gain-of-function allele Lrrk2G2019S (leucine-rich repeat kinase 2) promotes mitochondrial hyper-fission, depolarization, and oxidative stress in macrophages. In the presence of Lrrk2G2019S-dependent mitochondrial perturbations, AIM2 inflammasome activation promotes more cell death but not more pyroptotic IL-1b release. Instead, inflammasome activation in Lrrk2G2019S macrophages triggers gasdermin D (GSDMD)-mediated mitochondrial pores, driving up ROS-mediated RIPK1/RIPK3/MLKL dependent necroptosis. Consequently, infection of Lrrk2G2019S mice with Mycobacterium tuberculosis elicits hyperinflammation and immunopathology via enhanced neutrophil infiltration. By uncovering that GSDMD promotes non-pyroptotic cell death in Lrrk2G2019S macrophages, our findings demonstrate that altered mitochondrial function can reprogram cell death modalities to elicit distinct immune outcomes. This provides mechanistic insights into why mutations in LRRK2 are associated with susceptibility to chronic inflammatory and infectious diseases.HIGHLIGHTSAltered mitochondrial homeostasis reprograms cell death modalitiesGSDMD associates with and depolarizes mitochondrial membranes following AIM2 activationGSDMD initiates a shift from pyroptotic to necroptotic cell death in Lrrk2G2019S macrophagesLrrk2G2019S elicits hyperinflammation and susceptibility to infection in flies and mice

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The mtDNA replication-related genes TFAM and POLG are associated with leprosy in Han Chinese from Southwest China

Cited by 10 publications

References 65 publications

Missense Variants in HIF1A and LACC1 Contribute to Leprosy Risk in Han Chinese

Missense Variants in HIF1A and LACC1 Contribute to Leprosy Risk in Han Chinese

Mitochondrial HMG-Box Containing Proteins: From Biochemical Properties to the Roles in Human Diseases

Mitochondrial dysfunction promotes alternative gasdermin D-mediated inflammatory cell death and susceptibility to infection

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