Dysregulated expression of the gene EN1, or engrailed-1, due to a remarkable genetic mechanism, leads to a rare congenital disorder with severe limb malformations. This is reported in Nature by an international team of researchers from Charité Berlin, Switzerland, Brazil and other countries. They discovered a DNA region 300 kilobases away from EN1 which carries the information for a long non-coding RNA and is apparently needed for correct activation of the gene in limbs. At the start of their study, they investigated patients with complex malformations including severe shortening and deformation of the legs and feet and conjoined fingers. In the patients’ genomes, the researchers uncovered homozygous deletions on chromosome 2, spanning 27 to 63 kb, which affected the locus of a long noncoding RNA.

Long noncoding RNAs can be important components in gene regulation networks, but our knowledge about their precise role in the development of diseases has so far been very limited. A mouse model generated with the identified deletion in the study recapitulated the patients’ phenotype, and detailed functional analyses demonstrated that the deletion caused a complete loss of En1 activity in the limbs. Similar mechanisms involving long noncoding RNAs might be revealed in future in the development of other human diseases.