| First Author | Allou L | Year | 2021 |
| Journal | Nature | Volume | 592 |
| Issue | 7852 | Pages | 93-98 |
| PubMed ID | 33568816 | Mgi Jnum | J:306235 |
| Mgi Id | MGI:6710203 | Doi | 10.1038/s41586-021-03208-9 |
| Citation | Allou L, et al. (2021) Non-coding deletions identify Maenli lncRNA as a limb-specific En1 regulator. Nature 592(7852):93-98 |
| abstractText | Long non-coding RNAs (lncRNAs) can be important components in gene-regulatory networks(1), 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. |
