Non-coding deletions identify Maenli lncRNA as a limb-specific En1 regulator

Lila Allou, Sara Balzano, Andreas Magg, Mathieu Quinodoz, Beryl Royer-Bertrand, Robert Schöpflin, Wing-Lee Chan, Carlos E. Speck-Martins, Daniel Rocha 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 Ringel, Verena Heinrich, Giulia Cova, Guillaume Andrey, Cesar A. Prada-Medina, Rosanna Pescini-Gobert, Sheila Unger, Luisa Bonafé, Phillip Grote, Carlo Rivolta, Stefan Mundlos () and Andrea Superti-Furga
Additional contact information
Lila Allou: Max Planck Institute for Molecular Genetics
Sara Balzano: University of Lausanne
Andreas Magg: Max Planck Institute for Molecular Genetics
Mathieu Quinodoz: University of Lausanne
Beryl Royer-Bertrand: Lausanne University Hospital (CHUV) and University of Lausanne
Robert Schöpflin: Max Planck Institute for Molecular Genetics
Wing-Lee Chan: Charité-Universitätsmedizin Berlin
Carlos E. Speck-Martins: Genetic Unit, SARAH Network of Rehabilitation Hospitals
Daniel Rocha Carvalho: Genetic Unit, SARAH Network of Rehabilitation Hospitals
Luciano Farage: Instituto de Cardiologia do Distrito Federal
Charles Marques Lourenço: Centro Universitario Estácio
Regina Albuquerque: Faculdade Estadual de Medicina de São José do Rio Preto (FAMERP)
Srilakshmi Rajagopal: Tamil Nadu Dr M.G.R. Medical University
Sheela Nampoothiri: Amrita Institute of Medical Sciences & Research Centre
Belinda Campos-Xavier: Lausanne University Hospital (CHUV) and University of Lausanne
Carole Chiesa: Lausanne University Hospital (CHUV) and University of Lausanne
Florence Niel-Bütschi: Lausanne University Hospital (CHUV) and University of Lausanne
Lars Wittler: Max Planck Institute for Molecular Genetics
Bernd Timmermann: Max Planck Institute for Molecular Genetics
Malte Spielmann: Max Planck Institute for Molecular Genetics
Michael I. Robson: Max Planck Institute for Molecular Genetics
Alessa Ringel: Max Planck Institute for Molecular Genetics
Verena Heinrich: Max Planck Institute for Molecular Genetics
Giulia Cova: Max Planck Institute for Molecular Genetics
Guillaume Andrey: Max Planck Institute for Molecular Genetics
Cesar A. Prada-Medina: Max Planck Institute for Molecular Genetics
Rosanna Pescini-Gobert: University of Lausanne
Sheila Unger: Lausanne University Hospital (CHUV) and University of Lausanne
Luisa Bonafé: Lausanne University Hospital (CHUV) and University of Lausanne
Phillip Grote: Goethe University
Carlo Rivolta: University of Lausanne
Stefan Mundlos: Max Planck Institute for Molecular Genetics
Andrea Superti-Furga: Lausanne University Hospital (CHUV) and University of Lausanne

Nature, 2021, vol. 592, issue 7852, 93-98

Abstract: Abstract 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.

Date: 2021
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-021-03208-9 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:592:y:2021:i:7852:d:10.1038_s41586-021-03208-9

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-021-03208-9

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().