作者
Lila Allou,Sara Balzano,Andreas Magg,Mathieu Quinodoz,Beryl Royer-Bertrand,Robert Schöpflin,Wing Lee Chan,Carlos E. Speck-Martins,Daniel R. Carvalho,Luciano Farage,Charles Marques Lourenço,Regina Albuquerque,Srilakshmi Rajagopal,Sheela Nampoothiri,Belinda Campos-Xavier,Carole Chiesa,Florence Niel-Bütschi,Lars Wittler,Bernd Timmermann,Malte Spielmann,Michael I. Robson,Alessa R. Ringel,Verena Heinrich,Giulia Cova,Guillaume Andrey,Cesar Augusto Prada-Medina,Rosanna Pescini-Gobert,Sheila Unger,Luisa Bonafé,Phillip Grote,Carlo Rivolta,Stefan Mundlos,Andrea Superti-Furga
摘要
Long non-coding RNAs (lncRNAs) can be important components in gene-regulatory networks1, but the exact nature and extent of their involvement in human Mendelian disease is largely unknown. Here we show that genetic ablation of a lncRNA locus on human chromosome 2 causes a severe congenital limb malformation. We identified homozygous 27-63-kilobase deletions located 300 kilobases upstream of the engrailed-1 gene (EN1) in patients with a complex limb malformation featuring mesomelic shortening, syndactyly and ventral nails (dorsal dimelia). Re-engineering of the human deletions in mice resulted in a complete loss of En1 expression in the limb and a double dorsal-limb phenotype that recapitulates the human disease phenotype. Genome-wide transcriptome analysis in the developing mouse limb revealed a four-exon-long non-coding transcript within the deleted region, which we named Maenli. Functional dissection of the Maenli locus showed that its transcriptional activity is required for limb-specific En1 activation in cis, thereby fine-tuning the gene-regulatory networks controlling dorso-ventral polarity in the developing limb bud. Its loss results in the En1-related dorsal ventral limb phenotype, a subset of the full En1-associated phenotype. Our findings demonstrate that mutations involving lncRNA loci can result in human Mendelian disease.