title: 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: Unité INSERM U-781, Université Paris Descartes, Paris, France.
authors: Loïc
authors: L
authors: de Pontual
authors: Evelyn
authors: E
authors: Yao
authors: Patrick
authors: P
authors: Callier
authors: Laurence
authors: L
authors: Faivre
authors: Valérie
authors: V
authors: Drouin
authors: Sandra
authors: S
authors: Cariou
authors: Arie
authors: A
authors: Van Haeringen
authors: David
authors: D
authors: Geneviève
authors: Alice
authors: A
authors: Goldenberg
authors: Myriam
authors: M
authors: Oufadem
authors: Sylvie
authors: S
authors: Manouvrier
authors: Arnold
authors: A
authors: Munnich
authors: Joana Alves
authors: JA
authors: Vidigal
authors: Michel
authors: M
authors: Vekemans
authors: Stanislas
authors: S
authors: Lyonnet
authors: Alexandra
authors: A
authors: Henrion-Caude
authors: Andrea
authors: A
authors: Ventura
authors: Jeanne
authors: J
authors: Amiel
mesh_terms: D000818:Animals; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics; D030541:Databases, Genetic; D004380:Duodenal Obstruction / Q000235:genetics; D004622:Embryo, Mammalian; D004933:Esophageal Atresia / Q000235:genetics; D005143:Eyelids / Q000002:abnormalities; D005260:Female; D017353:Gene Deletion; D018095:Germ-Line Mutation; D057895:Haploinsufficiency; D006801:Humans; D008607:Intellectual Disability; D017880:Limb Deformities, Congenital / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008831:Microcephaly / Q000235:genetics; D023421:Models, Animal; D005810:Multigene Family; D041641:Musculoskeletal Development / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D014138:Tracheoesophageal Fistula
chemical_list: D035683:MicroRNAs