2021/02/10 by Lila Allou, Sara Balzano, Andreas Magg +30 · 2 citations
Biochemistry, Genetics and Molecular Biology · #Biology #Cancer-related molecular mechanisms research #Congenital limb and hand anomalies #Exon #Gene #Genetics #Limb bud #Limb development #Locus (genetics) #Phenotype #RNA Research and Splicing
paper · pdf · doi:10.1038/s41586-021-03208-9
openalex publication_date 2021/02/10 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/04
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. The long non-coding RNA locus Maenli controls mouse limb development by regulating En1 activity, and the absence of the homolgous MAENLI locus is associated with severe congenital limb defects in humans.