Insertion Mutation in Tnfrsf11a Causes a Paget's Disease–Like Phenotype in Heterozygous Mice and Osteopetrosis in Homozygous Mice

Alonso, Nerea; Wani, Sachin; Rose, Lorraine; Hof, R. J. vanʼt; Ralston, Stuart H.

doi:10.1002/jbmr.4288

Cited by 14 publications

(8 citation statements)

References 24 publications

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“…In a mutant mouse model with a nine-amino-acid insertion in Tnfrsf11a, the homozygotes develop osteopetrosis while the heterozygotes show osteolytic lesions. The abnormal RANK proteins in the mutant mice accumulated in Golgi apparatus and increased osteoclastogenesis by activating the unfolded protein response (Alonso et al, 2021). The findings suggest that the truncated or elongated RANK proteins generated in the first three cases of TNFRSF11A-associated DOS probably results in gain-offunction, which would be associated with the DOS phenotype.…”

Section: Resultsmentioning

confidence: 86%

A Null Mutation of TNFRSF11A Causes Dysosteosclerosis, Not Osteopetrosis

Kirkgöz

Özkan

Hazan³

et al. 2022

Front. Genet.

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Dysosteosclerosis (DOS) is a rare sclerosing bone dysplasia characterized by unique osteosclerosis of the long tubular bones and platyspondyly. DOS is inherited in an autosomal recessive manner and is genetically and clinically heterogeneous. To date, four individuals with DOS who have five different TNFRSF11A mutations have been reported. Based on their data, it is hypothesized that mutations producing aberrant mutant RANK proteins (missense or truncated or elongated) cause DOS, while null mutations lead to osteopetrosis, autosomal recessive 7 (OPTB7). Herein, we present the fifth case of TNFRSF11A-associated DOS with a novel homozygous frame-shift mutation (c.19_31del; p.[Arg7CysfsTer172]). The mutation is predicted to cause nonsense mutation-mediated mRNA decay (NMD) in all RANK isoform transcripts, resulting in totally null allele. Our findings suggest genotype-phenotype relationship in TNFRSF11A-associated OPTB7 and DOS remains unclear, and that the deficiency of TNFRSF11A functions might cause DOS, rather than osteopetrosis. More data are necessary to understand the phenotypic spectrum caused by TNFRSF11A mutations.

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Section: Resultsmentioning

confidence: 86%

A Null Mutation of TNFRSF11A Causes Dysosteosclerosis, Not Osteopetrosis

Kirkgöz

Özkan

Hazan³

et al. 2022

Front. Genet.

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“…This finding is similar to previous report that different phenotypes existed in homozygous and heterozygous mutations of TNFRSF11A in mice. 42 With a P value of 0.168 in homozygous mutation rs35208462 C>T, the insufficient number of participants may also compromise the power of statistical analysis. The relationship between ESCC and mutant heterozygote of rs77387752 is not statically significant as well, which may be due to the mode of inheritance and mechanism of SNPs in tumorigenesis and development.…”

Section: Discussionmentioning

confidence: 99%

The Single Nucleotide Polymorphisms of AP1S1 are Associated with Risk of Esophageal Squamous Cell Carcinoma in Chinese Population

Fang

et al. 2022

PGPM

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Background The σ1A subunit of the adaptor protein 1 (AP1S1) participates in various intracellular transport pathways, especially the maintenance of copper homeostasis, which is pivotal in carcinogenesis. It is therefore rational to presume that AP1S1 might also be involved in carcinogenesis. In this hospital-based case-control study, we investigated the genetic susceptibility to ESCC in relation to SNPs of AP1S1 among Chinese population. Methods A database containing a total of 1303 controls and 1043 ESCC patients were retrospectively studied. The AP1S1 SNPs were analyzed based on ligation detection reaction (LDR) method. Then, the relationship between ESCC and SNPs of AP1S1 was determined with a significant crude P<0.05. Then the logistic regression analysis was used for the calculation for adjusted P in the demographic stratification comparison if a significant difference was observed in the previous step. Results AP1S1 rs77387752 C>T genotype TT was an independent risk factor for ESCC, while rs4729666 C>T genotype TC and rs35208462 C>T genotype TC were associated with a lower risk for ESCC, especially in co-dominant model and allelic test for younger, male subjects who are not alcohol-drinkers nor cigarette smokers. Conclusion AP1S1 rs77387752, rs4729666 and rs35208462 polymorphisms are associated with susceptibility to ESCC in Chinese individuals. AP1S1 SNPs may exert an important role in esophageal carcinogenesis and could serve as potential diagnostic biomarkers.

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“…TNFRSF11A is a member of the tumor necrosis factor receptor superfamily, which interacts with a variety of TRAF family proteins to induce the activation of NF-Kappa B and MAPK signaling pathway, and is also an important mediator of osteoclast development (20)(21)(22)(23). CSF1 can stimulate CSF1R to promote the proliferation and differentiation of macrophages and the formation of osteoclasts, so in patients with KOA, inhibition of CSF1R is bene cial (24)(25)(26).…”

Section: Discussionmentioning

confidence: 99%

Identification of Genes and Pathways of Nonsteroidal Anti-Inflammatory Drugs Acting on Synovia from Women with Knee Osteoarthritis by Bioinformatics Analysis

Zhao

Wang

Dong

et al. 2021

Preprint

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Purpose: Through the bioinformatics analysis, to identify the genes and pathways of nonsteroidal anti-inflammatory drugs(NSAIDs) acting on synovia from women with knee osteoarthritis (KOA), and to provide reference for clinical application. Methods: We downloaded the gene microarray datasets with the accession number of GSE55457 and GSE55584 from the Gene Expression Omnibus (GEO; https://www.ncbi.nlm.nih.gov/geo/) database, including 5 untreated KOA patients, 9 NSAIDs treated KOA patients and 2 patients without KOA The samples in the untreated KOA group and the NSAIDs treated KOA group were used for main analysis. The samples in the untreated KOA group and the normal control group were used for cooperative analysis. Then we performed robust multi-array (RMA) normalization with affy R programming package. After that, differential expression genes (DEGs) in main analysis and cooperative analysis were identified based on limma package separately. Screening the common DEGs from main analysis and cooperative analysis. Enriched gene ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of DEGs were obtained through the Database for Annotation, Visualization and Integrated Discovery (DAVID). What's more, protein-protein interaction (PPI) network was constructed, and we identified modules of PPI network through Cytoscape to screen valuable targets. The value of gene expression fold change (FC) ≥1.4 or ≤1/1.4, and P <0.05 were used as the screening conditions. P <0.05 and Associated genes count>5 were used as the screening conditions. Results: There were 338 DEGs in main analysis. Among them, 211 genes were up-regulated and 127 genes were down-regulated. There were 7005 DEGs in cooperative analysis. Among them, 6952 genes were up-regulated and 53 genes were down-regulated. A total of 129 common DEGs were identified between main analysis and cooperative analysis. There are 2 biological processes, 3 cell components and 2 molecular functions for the enrichment of differentially expressed genes. Conclusion: NSAIDs may play a certain role in synovia from women with KOA by regulating the mRNA expressions of il-6, TNFRSF11A and CSF1R, which may become one of the indicators for monitoring the efficacy of NSAIDs.

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Insertion Mutation in Tnfrsf11a Causes a Paget's Disease–Like Phenotype in Heterozygous Mice and Osteopetrosis in Homozygous Mice

Abstract: This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as

Cited by 14 publications

References 24 publications

A Null Mutation of TNFRSF11A Causes Dysosteosclerosis, Not Osteopetrosis

A Null Mutation of TNFRSF11A Causes Dysosteosclerosis, Not Osteopetrosis

The Single Nucleotide Polymorphisms of AP1S1 are Associated with Risk of Esophageal Squamous Cell Carcinoma in Chinese Population

Identification of Genes and Pathways of Nonsteroidal Anti-Inflammatory Drugs Acting on Synovia from Women with Knee Osteoarthritis by Bioinformatics Analysis

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