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

Nature Medicine
Giedre GrigelionieneTatsuya Kobayashi

Abstract

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 th...Continue Reading

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Citations

Oct 22, 2019·American Journal of Medical Genetics. Part a·Geert R MortierMatthew L Warman
Mar 15, 2020·Genes·Sayed Haidar Abbas RazaLinsen Zan
Oct 28, 2019·Frontiers in Genetics·Olga PlotnikovaMikhail Skoblov
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Dec 6, 2021·Cancer Science·Hiroshi I Suzuki, Koh Onimaru

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Datasets Mentioned

BETA
GSM1112777
GSM772791
GSM670044
GSM772781

Methods Mentioned

BETA
exome sequencing
RNA-seq
immunoprecipitation
CLIP
seCLIP
X-ray
PCR
dissection
iCLIP
transfection

Software Mentioned

Agilent Genomic Workbench
bowtie
seCLIP
R
STAR
Genome Analysis Tool ( GATK
Fiji
MOSAIK
Cutadapt
ANNOVAR

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