Non-coding deletions identify Maenli lncRNA as a limb-specific En1 regulator
Authors
- L. Allou
- S. Balzano
- A. Magg
- M. Quinodoz
- B. Royer-Bertrand
- R. Schöpflin
- W.L. Chan
- C.E. Speck-Martins
- D.R. Carvalho
- L. Farage
- C.M. Lourenço
- R. Albuquerque
- S. Rajagopal
- S. Nampoothiri
- B. Campos-Xavier
- C. Chiesa
- F. Niel-Bütschi
- L. Wittler
- B. Timmermann
- M. Spielmann
- M.I. Robson
- A. Ringel
- V. Heinrich
- G. Cova
- G. Andrey
- C.A. Prada-Medina
- R. Pescini-Gobert
- S. Unger
- L. Bonafé
- P. Grote
- C. Rivolta
- S. Mundlos
- A. Superti-Furga
Journal
- Nature
Citation
- Nature 592 (7852): 93-98
Abstract
Long non-coding RNAs (lncRNAs) can be important components in gene-regulatory networks, 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.