ESPEYB16 5. Bone, Growth Plate and Mineral Metabolism New Insight into Rare Skeletal Disorders (4 abstracts)
5.6. Gain-of-function mutation of microRNA-140 in human skeletal dysplasia
Grigelioniene G , Suzuki HI , Taylan F , Mirzamohammadi F , Borochowitz ZU , Ayturk UM , Tzur S , Horemuzova E , Lindstrand A , Weis MA , Grigelionis G , Hammarsjö A , Marsk E , Nordgren A , Nordenskjöld M , Eyre DR , Warman ML , Nishimura G , Sharp PA & Kobayashi T
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden & Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
Abstract: Nat Med. 2019 Apr;25(4):583–590. PMID: 30804514
In brief: This study describes the first skeletal dysplasia caused by a mutation in a microRNA that is not simply inactivating, but modifies the repertoire of target genes.
Comment: MicroRNAs (miRNAs) are small (20–24 nucleotides) noncoding RNA molecules that post-transcriptionally regulate gene expression. There are about 2000 known microRNAs and each targets several genes. Therefore, microRNAs are involved in the regulation in many, if not all, cellular functions.
MicroRNA-140, miR140, is abundantly and almost exclusively expressed in chondrocytes. miR140 knockout mice exhibit dwarfism and craniofacial dysmorphism due to accelerated hypertrophic differentiation and therefore accelerated endochondral ossification.
In this study, the authors describe a novel skeletal dysplasia and show strong evidence for a causative miR-140 mutation. However, in contrast to that expected with loss of function of miR-140, the novel dysplasia exhibited delayed bone maturation. The authors found that the skeletal phenotype was replicated when the identified nucleotide substitution was introduced in mice and was distinct from the phenotype of miR-140 complete knockout mice, indicating that the nucleotide substitution does not result in a simple loss-of-function. Instead, the mutant miR-140 caused de-repression of wild-type miR-140 target genes and repression of a new set of target genes. This report thus identifies the first skeletal dysplasia that is caused by a complex combination of gain- and loss-of-function effects of a microRNA mutation and expands our understanding of the mechanisms by which mutations in non-coding micro RNAs can contribute to human disease.
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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