期刊
NATURE MEDICINE
卷 25, 期 4, 页码 583-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41591-019-0353-2
关键词
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资金
- Science for Life Laboratory, the National Genomics Infrastructure (NGI), Sweden, SNIC through UPPMAX [b2014231]
- NIH [P30 AR066261]
- Stockholm County Council [20150143, 20130315]
- National Institutes of Health (National Institute of Arthritis and Musculoskeletal and Skin Diseases) [R01-AR056645]
- National Institutes of Health (National Institute of General Medical Sciences) [R01-GM034277]
- National Institutes of Health (National Cancer Institute) [R01-CA133404, P30-CA14051]
- Eli Lilly International Corporation
- Fernstrom Foundation
- Karolinska Institutet
- Swedish Society of Medicine
- Stiftelsen Samariten, Stockholm, Sweden
- Promobilia and Frimurare Barnhuset Stockholm
- Swedish Research Council [2018-03046]
- Uehara Memorial Foundation Research Fellowship
- Osamu Hayaishi Memorial Scholarship for Study Abroad
- Swedish Research Council [2018-03046] Funding Source: Swedish Research Council
- Vinnova [2018-03046] Funding Source: Vinnova
MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression. Heterozygous loss-of-function point mutations of miRNA genes are associated with several human congenital disorders(1-5), but neomorphic (gain-of-new-function) mutations in miRNAs due to nucleotide substitutions have not been reported. Here we describe a neomorphic seed region mutation in the chondrocyte-specific, super-enhancer-associated MIR140 gene encoding microRNA-140 (miR-140) in a novel autosomal dominant human skeletal dysplasia. Mice with the corresponding single nucleotide substitution show skeletal abnormalities similar to those of the patients but distinct from those of miR-140-null mice(6). This mutant miRNA gene yields abundant mutant miR-140-5p expression without miRNA-processing defects. In chondrocytes, the mutation causes widespread derepression of wild-type miR-140-5p targets and repression of mutant miR-140-5p targets, indicating that the mutation produces both loss-of-function and gain-of-function effects. Furthermore, the mutant miR-140-5p seed competes with the conserved RNA-binding protein Ybx1 for overlapping binding sites. This finding may explain the potent target repression and robust in vivo effect by this mutant miRNA even in the absence of evolutionary selection of miRNA-target RNA interactions, which contributes to the strong regulatory effects of conserved miRNAs(7,8). Our study presents the first case of a pathogenic gain-of-function miRNA mutation and provides molecular insight into neomorphic actions of emerging and/or mutant miRNAs.
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