Gain-of-function mutation of microRNA-140 in human skeletal dysplasia
| Autor: | Shay Tzur, Hiroshi I. Suzuki, Gen Nishimura, Ann Nordgren, David R. Eyre, Elin Marsk, Ugur M. Ayturk, MaryAnn Weis, Giedre Grigelioniene, Fulya Taylan, Zvi Borochowitz, Eva Horemuzova, Tatsuya Kobayashi, Matthew L. Warman, Anna Lindstrand, Gintautas Grigelionis, Magnus Nordenskjöld, Anna Hammarsjö, Phillip A. Sharp, Fatemeh Mirzamohammadi |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Mutant Biology medicine.disease_cause Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Chondrocytes 0302 clinical medicine microRNA Gene expression medicine Animals Humans Gain of function mutation Gene Psychological repression Derepression Genetics Bone Diseases Developmental Mutation Base Sequence Point mutation Homozygote General Medicine medicine.disease Mice Mutant Strains Pedigree Mice Inbred C57BL MicroRNAs Phenotype 030104 developmental biology Dysplasia Gain of Function Mutation 030220 oncology & carcinogenesis Cancer research Female Transcriptome |
| Zdroj: | Nature medicine |
| ISSN: | 1546-170X 1078-8956 |
| Popis: | MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression. Heterozygous loss-of-function point mutations of miRNA genes are associated with several human congenital disorders1-5, 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 mice6. 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 miRNAs7,8. 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. |
| Databáze: | OpenAIRE |
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