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Germline deletion of the miR-17∼92 cluster causes skeletal and growth defects in humans

Nature Genetics volume 43, pages 1026–1030 (2011)Cite this article

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Abstract

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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Figure 1: Clinical features of individuals with 13q31.3 deletions.
Figure 2: Mapping 13q31.3 microdeletions in individuals with Feingold syndrome.
Figure 3: miR-17∼92Δ/+ mice display features of Feingold syndrome.
Figure 4: Widespread skeletal defects in E18.5 miR-17∼92Δ/Δ embryos.

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Acknowledgements

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.

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Author notes

  1. Loïc de Pontual, Evelyn Yao, Andrea Ventura and Jeanne Amiel: These authors contributed equally to this work.

Authors and Affiliations

  1. Unité INSERM U-781, Université Paris Descartes, Paris, France

    Loïc de Pontual, Sandra Cariou, Myriam Oufadem, Arnold Munnich, Michel Vekemans, Stanislas Lyonnet, Alexandra Henrion-Caude & Jeanne Amiel

  2. Services de Pédiatrie, Hôpital Jean Verdier, Université Paris XIII, Assistance Publique-Hôpitaux de Paris (AP-HP), Bondy, France

    Loïc de Pontual

  3. Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Evelyn Yao, Joana Alves Vidigal & Andrea Ventura

  4. Service de Génétique, Hôpital d'enfants, Dijon, France

    Patrick Callier & Laurence Faivre

  5. Service de Génétique, Hôpital Charles Nicolle, Rouen, France

    Valérie Drouin & Alice Goldenberg

  6. Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands

    Arie Van Haeringen

  7. Service de Génétique, Hôpital Arnaud de Villeneuve, Montpellier, France

    David Geneviève

  8. Service de Génétique Clinique, Hôpital J. de Flandre, Lille, France

    Sylvie Manouvrier

  9. Services de Génétique et Cytogénétique, Hôpital Necker-Enfant Malades, AP-HP, Paris, France

    Arnold Munnich, Stanislas Lyonnet & Jeanne Amiel

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  1. Loïc de Pontual
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Contributions

L.d.P., P.C., S.C. and M.O. performed subject-related experiments. E.Y. performed the analysis of miR-17∼92 mutant mice, the ChIP experiments and determined miR-17∼92 expression in subjects. J.A.V. determined miR-17∼92 expression in mouse embryos. J.A. and A.V. designed and supervised the project and wrote the manuscript. A.M., M.V., S.L., L.d.P., E.Y. and A.H.-C. provided critical input into project development and manuscript preparation. All other coauthors identified subjects with Feingold syndrome and performed related clinical and laboratory studies (L.F., V.D., A.V.H., D.G., A.G. and S.M.).

Corresponding authors

Correspondence to Andrea Ventura or Jeanne Amiel.

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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). https://doi.org/10.1038/ng.915

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