Dataset Information

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

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 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.

SUBMITTER: Grigelioniene G

PROVIDER: S-EPMC6622181 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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

Grigelioniene Giedre G Suzuki Hiroshi I HI Taylan Fulya F Mirzamohammadi Fatemeh F Borochowitz Zvi U ZU Ayturk Ugur M UM Tzur Shay S Horemuzova Eva E Lindstrand Anna A Weis Mary Ann MA Grigelionis Gintautas G Hammarsjö Anna A Marsk Elin E Nordgren Ann A Nordenskjöld Magnus M Eyre David R DR Warman Matthew L ML Nishimura Gen G Sharp Phillip A PA Kobayashi Tatsuya T

Nature medicine 20190225 4

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<sup>1-5</sup>, 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 ...[more]

PMID: 30804514

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Project description:BACKGROUND: AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme that is evolutionarily conserved from yeast to mammals and functions to maintain cellular and whole body energy homeostasis. Studies in experimental animals demonstrate that activation of AMPK in skeletal muscle protects against insulin resistance, type 2 diabetes and obesity. The regulatory gamma(3) subunit of AMPK is expressed exclusively in skeletal muscle; however, its importance in controlling overall AMPK activity is unknown. While evidence is emerging that gamma subunit mutations interfere specifically with AMP activation, there remains some controversy regarding the impact of gamma subunit mutations. Here we report the first gain-of-function mutation in the muscle-specific regulatory gamma(3) subunit in humans. METHODS AND FINDINGS: We sequenced the exons and splice junctions of the AMPK gamma(3) gene (PRKAG3) in 761 obese and 759 lean individuals, identifying 87 sequence variants including a novel R225W mutation in subjects from two unrelated families. The gamma(3) R225W mutation is homologous in location to the gamma(2)R302Q mutation in patients with Wolf-Parkinson-White syndrome and to the gamma(3)R225Q mutation originally linked to an increase in muscle glycogen content in purebred Hampshire Rendement Napole (RN-) pigs. We demonstrate in differentiated muscle satellite cells obtained from the vastus lateralis of R225W carriers that the mutation is associated with an approximate doubling of both basal and AMP-activated AMPK activities. Moreover, subjects bearing the R225W mutation exhibit a approximately 90% increase of skeletal muscle glycogen content and a approximately 30% decrease in intramuscular triglyceride (IMTG). CONCLUSIONS: We have identified for the first time a mutation in the skeletal muscle-specific regulatory gamma(3) subunit of AMPK in humans. The gamma(3)R225W mutation has significant functional effects as demonstrated by increases in basal and AMP-activated AMPK activities, increased muscle glycogen and decreased IMTG. Overall, these findings are consistent with an important regulatory role for AMPK gamma(3) in human muscle energy metabolism.

Dataset Information

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

Publications

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

Similar Datasets

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