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

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 deafness, 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.

• Authors: Loïc de Pontual, Evelyn Yao, Patrick Callier, Laurence Faivre, Valérie Drouin, Sandra Cariou, Arie Van Haeringen, David Geneviève, Alice Goldenberg, Myriam Oufadem, Sylvie Manouvrier, Arnold Munnich, Joana Alves Vidigal, Michel Vekemans, Stanislas Lyonnet, Alexandra Henrion-Caude, Andrea Ventura, Jeanne Amiel
• Journal: Nature genetics (Nat Genet) Vol. 43 Issue 10 Pg. 1026-30 (Sep 04 2011) ISSN: 1546-1718 [Electronic] United States
• PMID: 21892160 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• MicroRNAs

Topics

• Animals
• Chromosomes, Human, Pair 13 (genetics)
• Databases, Genetic
• Duodenal Obstruction (genetics)
• Embryo, Mammalian
• Esophageal Atresia (genetics)
• Eyelids (abnormalities)
• Female
• Gene Deletion
• Germ-Line Mutation
• Haploinsufficiency
• Humans
• Intellectual Disability
• Limb Deformities, Congenital (genetics)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• MicroRNAs (genetics, metabolism)
• Microcephaly (genetics)
• Models, Animal
• Multigene Family
• Musculoskeletal Development (genetics)
• Pedigree
• Polymerase Chain Reaction
• Tracheoesophageal Fistula