Journal Article

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

Van Haeringen, Arie, Lyonnet, Stanislas, Yao, Evelyn, Cariou, Sandra, Oufadem, Myriam, Goldenberg, Alice, Geneviève, David, Vidigal, Joana Alves, Faivre, Laurence, Drouin, Valérie, Henrion-Caude, Alexandra, Ventura, Andrea, de Pontual, Loïc, Vekemans, Michel, Callier, Patrick, Munnich, Arnold, Amiel, Jeanne, Manouvrier, Sylvie

2011

Overview

Andrea Ventura and colleagues report germline hemizygous deletions in the miR-17~92 cluster in individuals with features overlapping Feingold syndrome. Mice with targeted deletions in miR17~92 also display growth and skeletal defects. 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 1 , 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/2489/144 / 631/337/384/331 / 692/699/1670/1669 / Agriculture / Animal Genetics and Genomics / Animals / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer Research / Chromosomes, Human, Pair 13 - genetics / Databases, Genetic / Deafness / Duodenal Obstruction - genetics / Embryo, Mammalian / Esophageal Atresia - genetics / Experiments / Eyelids - abnormalities / Female / Fundamental and applied biological sciences. Psychology / Gene Deletion / Gene expression / Gene Function / Genetic aspects / Genetic disorders / Genetics of eukaryotes. Biological and molecular evolution / Genomes / Germ-Line Mutation / Grants / Haploinsufficiency / Human Genetics / Humans / Intellectual Disability / letter / Limb Deformities, Congenital - genetics / Male / Mice / Mice, Inbred C57BL / Mice, Knockout / Microcephaly - genetics / MicroRNA / MicroRNAs - genetics / MicroRNAs - metabolism / Models, Animal / Multigene Family / Musculoskeletal Development - genetics / Mutation / Pedigree / Physiological aspects / Polymerase Chain Reaction / Risk factors / Tracheoesophageal Fistula