Gain-of-function mutation of microRNA-140 in human skeletal dysplasia

Nat Med. 2019 Apr;25(4):583-590. doi: 10.1038/s41591-019-0353-2. Epub 2019 Feb 25.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Bone Diseases, Developmental / genetics*
  • Chondrocytes / metabolism
  • Female
  • Gain of Function Mutation / genetics*
  • Homozygote
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Pedigree
  • Phenotype
  • Transcriptome / genetics


  • MicroRNAs
  • Mirn140 microRNA, human