更新于：2024-11-01

RNR1

更新于：2024-11-01

基本信息

别名

RNA, ribosomal 45S cluster 1、RNR1

简介-

关联

项与 RNR1 相关的药物

LOR-2501

靶点

RNR1 x 核糖核苷酸还原酶复合体

作用机制

RNR抑制剂 [+1]

在研机构-

原研机构

Aptose Biosciences, Inc.

在研适应症-

非在研适应症

肾肿瘤 [+2]

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 RNR1 相关的临床结果

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100 项与 RNR1 相关的转化医学

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0 项与 RNR1 相关的专利（医药）

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107

项与 RNR1 相关的文献（医药）

2024-11-01·Mitochondrion

Association analysis of mitochondrial DNA heteroplasmic variants: Methods and application

Article

作者: Vasan, Ramachandran S. ; Arking, Dan E. ; Psaty, Bruce M ; Pitsillides, Achilleas N ; Satizabal, Claudia L. ; Rotter, Jerome I ; Vasan, Ramachandran S ; Abecasis, Goncalo ; Arking, Dan E ; Liu, Xue ; Bulekova, Katia ; Boerwinkle, Eric ; Raffield, Laura M ; Levy, Daniel ; Ding, Jun ; Sun, Xianbang ; Psaty, Bruce M. ; Liu, Chunyu ; Carson, April P. ; Satizabal, Claudia L ; Fitzpatrick, Annette L. ; Fitzpatrick, Annette L ; Zhang, Yuankai ; Yang, Jian ; Pitsillides, Achilleas N. ; Bis, Joshua C ; Yong, Qian ; Rich, Stephen S ; Lai, Meng ; Rich, Stephen S. ; Guo, Xiuqing ; Raffield, Laura M. ; Bis, Joshua C. ; Carson, April P ; Rotter, Jerome I.

We rigorously assessed a comprehensive association testing framework for heteroplasmy, employing both simulated and real-world data. This framework employed a variant allele fraction (VAF) threshold and harnessed multiple gene-based tests for robust identification and association testing of heteroplasmy. Our simulation studies demonstrated that gene-based tests maintained an appropriate type I error rate at α = 0.001. Notably, when 5 % or more heteroplasmic variants within a target region were linked to an outcome, burden-extension tests (including the adaptive burden test, variable threshold burden test, and z-score weighting burden test) outperformed the sequence kernel association test (SKAT) and the original burden test. Applying this framework, we conducted association analyses on whole-blood derived heteroplasmy in 17,507 individuals of African and European ancestries (31 % of African Ancestry, mean age of 62, with 58 % women) with whole genome sequencing data. We performed both cohort- and ancestry-specific association analyses, followed by meta-analysis on both pooled samples and within each ancestry group. Our results suggest that mtDNA-encoded genes/regions are likely to exhibit varying rates in somatic aging, with the notably strong associations observed between heteroplasmy in the RNR1 and RNR2 genes (p < 0.001) and advance aging by the Original Burden test. In contrast, SKAT identified significant associations (p < 0.001) between diabetes and the aggregated effects of heteroplasmy in several protein-coding genes. Further research is warranted to validate these findings. In summary, our proposed statistical framework represents a valuable tool for facilitating association testing of heteroplasmy with disease traits in large human populations.

2024-08-09·Muscle & nerve

Mitochondrial genome variants associated with amyotrophic lateral sclerosis and their haplogroup distribution.

Article

作者: Briones, Marcelo R S ; Ferreira, Renata C ; Broach, James R ; Antoneli, Fernando M ; Schneper, Lisa ; Campos, João H ; Santos, Ilda M

INTRODUCTION/AIMSAmyotrophic lateral sclerosis (ALS) may be familial or sporadic, and twin studies have revealed that even sporadic forms have a significant genetic component. Variants in 55 nuclear genes have been associated with ALS and although mitochondrial dysfunction is observed in ALS, variants in mitochondrial genomes (mitogenomes) have not yet been tested for association with ALS. The aim of this study was to determine whether mitogenome variants are associated with ALS.METHODSWe conducted a genome-wide association study (GWAS) in mitogenomes of 1965 ALS patients and 2547 controls.RESULTSWe identified 51 mitogenome variants with p values <10^-7, of which 13 had odds ratios (ORs) >1, in genes RNR1, ND1, CO1, CO3, ND5, ND6, and CYB, while 38 variants had OR <1 in genes RNR1, RNA2, ND1, ND2, CO2, ATP8, ATP6, CO3, ND3, ND4, ND5, ND6, and CYB. The frequencies of haplogroups H, U, and L, the most frequent in our ALS data set, were the same in different onset sites (bulbar, limb, spinal, and axial). Also, intra-haplogroup GWAS revealed unique ALS-associated variants in haplogroups L and U.DISCUSSIONOur study shows that mitogenome single nucleotide variants (SNVs) are associated with ALS and suggests that these SNVs could be included in routine genetic testing for ALS and that mitochondrial replacement therapy has the potential to serve as a basis for ALS treatment.

2024-06-01·Therapies

Pharmacogénétique de l’ototoxicité des aminosides : état des connaissances et des pratiques – recommandations du Réseau francophone de pharmacogénétique (RNPGx)

Article

作者: Picard, Nicolas ; Boyer, Jean-Christophe ; Trimouille, Aurélien ; Baklouti, Sarah ; Becquemont, Laurent ; Dhaenens, Claire-Marie ; Hennart, Benjamin ; Lebreton, Louis

The administration of aminoglycosides can induce nephrotoxicity or ototoxicity, which can be monitored through pharmacological therapeutic drug monitoring. However, there are cases of genetic predisposition to ototoxicity related to the MT-RNR1 gene, which may occur from the first administrations. Pharmacogenetic analysis recommendations have recently been proposed by the Clinical Pharmacogenetics Implementation Consortium (CPIC). The Francophone Pharmacogenetics Network (RNPGx) provides a bibliographic synthesis of this genetic predisposition, as well as professional recommendations. The MT-RNR1 gene codes for mitochondrial 12S rRNA, which constitutes the small subunit of the mitochondrial ribosome. Three variants can be identified: the variants m.1555A>G and m.1494C>T of the MT-RNR1 gene have a 'high' level of evidence regarding the risk of ototoxicity. The variant m.1095T>C has a 'moderate' level of evidence. The search for these variants can be performed in the laboratory if the administration of aminoglycosides can be delayed after obtaining the result. However, if the treatment is urgent, there is currently no rapid test available in France (a 'point-of-care' test is authorized in Great Britain). RNPGx considers: (1) the search for the m.1555A>G, m.1494C>T variants as 'highly recommended' and the m.1095T>C variant as 'moderately recommended' before the administration of an aminoglycoside (if compatible with the medical context). It should be noted that the level of heteroplasmy detected does not modify the recommendation; (2) pharmacogenetic analysis is currently not feasible in situations of short-term aminoglycoside administration, in the absence of an available analytical solution (rapid test to be evaluated in France); (3) the retrospective analysis in case of aminoglycoside-induced ototoxicity is 'recommended'; (4) analysis of relatives is 'recommended'. Through this summary, RNPGx proposes an updated review of the MT-RNR1-aminoglycoside gene-drug pair to serve as a basis for adapting practices regarding pharmacogenetic analysis related to aminoglycoside treatment.