MicroRNAs (miRNAs) are key regulators of gene expression in animals and plants. Studies in a variety of model organisms show that miRNAs modulate developmental processes. To our knowledge, the only hereditary condition known to be caused by a miRNA is a form of adult-onset non-syndromic deafness1, and no miRNA mutation has yet been found to be responsible for any developmental defect in humans. Here we report the identification of germline hemizygous deletions of MIR17HG, encoding the miR-17∼92 polycistronic miRNA cluster, in individuals with microcephaly, short stature and digital abnormalities. We demonstrate that haploinsufficiency of miR-17∼92 is responsible for these developmental abnormalities by showing that mice harboring targeted deletion of the miR-17∼92 cluster phenocopy several key features of the affected humans. These findings identify a regulatory function for miR-17∼92 in growth and skeletal development and represent the first example of an miRNA gene responsible for a syndromic developmental defect in humans.
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We are thankful to the subjects and their referent doctors for their active participation in this study. We are also particularly thankful to P. Hurlin for generously providing forelimbs of Mycn conditional knockout mouse embryos. This work was supported by grants from the Agence Nationale de la Recherche (ANR grant EvoDevoMut), the Foundation pour la Recherche Médicale (FRM), the Institut National du Cancer-Direction de l'Hospitalisation et de l'Organisation des soins (INCa-DHOS), and the Institut National du Cancer. Work in the laboratory of A.V. was funded by US National Institutes of Health (NIH)-National Cancer Institute (NCI) grant R01CA149707, a Sidney Kimmel Award and a Geoffrey Beene Research Grant. E.Y. is a recipient of the NIH Molecular and Cellular Biology T32 training grant. We thank L. Selleri for her expertise in the phenotypic analysis of miR-17∼92–mutant mice skeletons, L. Legeai-Mallet, A. Pelet and P. Ogrodowski for helpful discussion and technical advice and J. Hollenstein for editing the manuscript.
The authors declare no competing financial interests.
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de Pontual, L., Yao, E., Callier, P. et al. Germline deletion of the miR-17∼92 cluster causes skeletal and growth defects in humans. Nat Genet 43, 1026–1030 (2011) doi:10.1038/ng.915
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