Research gives new insights in the development of rare diseases

An epigenetic mechanism for gene regulation described for the first time provides new insights into the development and etiology of rare diseases.

Tue, 2021 / 03 / 02
An international team of researchers from Berlin and Lausanne discovered a novel epigenetic mechanism as the cause of a very rare disease that leads to pronounced malformations of the arms and legs in affected patients. In the journal Nature, the researchers describe how a previously unstudied section in the non-coding region of the genome regulates a gene required for development, offering new insights into the possible cause of other rare hereditary diseases (1).

Since the human genome was completely sequenced for the first time 20 years ago, much has changed in medical research. For a long time, the focus in the field of genetics was on the so-called coding sequences. There are about 20,000 such genes in the human genome that provide the blueprint for proteins. Twenty years ago, this was initially a surprise, because even the Human Genome Project itself assumed as late as 2001 that there were up to 40,000 genes, and other estimates even exceeded this assumption (2). However, these coding sequences account for only about 2% of the total human genome. The non-coding regions between these genes, constituting 98% of the human genome, have long been regarded as useless ballast that needlessly accumulated during evolution and thus has been neglected by research – wrongly, as has been shown over time: many of these regions are of crucial importance, for example, in precisely regulating the activity of genes. For specifically this regulation, Dr. Lila Allou et al. have discovered a new mechanism in which a non-coding section upstream of the gene engrailed-1 (En1) must be read in order to switch on this gene and form the corresponding protein (1,3).

The role of the En1 gene has long been known for the development of the cerebellum, the midbrain and the dorsoventral orientation of the outer limbs (4). If the function of the gene is disturbed by mutations, corresponding malformations are found in affected patients. However, physicians in Brazil and India first reported three unrelated patients who had normal brain development but whose extremities were severely deformed: for example, their legs were severely shortened, and their knees were not oriented forward, their fingers were partially fused together, and nails were on the underside of the fingers. An analysis of the genome revealed homozygous deletions of non-coding sequences at the same positions upstream of En1 in each of the patients - the gene itself was not affected.

In collaboration with researchers from the Charité in Berlin, scientist Dr. Lila Allou at the Max Planck Institute for Molecular Genetics identified a previously undescribed non-coding transcript (lncRNA) in this region. In a mouse model, the researchers investigated and identified the role of this non-coding region in the regulation of En1. Consequently, they named it Maenli, for master regulator of En1 in the limb. They were able to demonstrate that Maenli is required during embryonic development in the limb of mice for the activation of En1 and thus the orientation and correct formation of the limb. Surprisingly, the sequence of Maenli itself appears less important for this function than its targeted expression. Thus, an alternative sequence inserted at the same site could already reduce the extent of malformations.

The exact mechanism behind the activation of En1 through the expression of Maenli is not yet fully understood and is being further investigated. However, it is already clear once again how important the role of non-coding sequences in the genome is. Genetic variants in this comprehensive area are responsible for many other genetic diseases that have so far eluded our comprehension. Elucidating their causes would facilitate diagnosis for affected patients and possibly also pave the way for new therapeutic options for some diseases.

Rare diseases are of particular interest to us at SKC. You will therefore also find many other blog articles on the topic of rare diseases, especially on Rare Disease Day 2021.

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(1) Allou L, et al. (2021) Noncoding deletions identify Maenli lncRNA as a limb specific En1 regulator. Nature.



(4) Wurst W, et al. (1994). Multiple developmental defects in Engrailed-1 mutant mice: an early mid-hindbrain deletion and patterning defects in forelimbs and sternum. Development.

About the author

Ihr Ansprechpartner Dr. rer. nat. Daniel Brand
Dr. rer. nat. Daniel Brand
M. Sc. Biomedicine
Fon: +49 511 64 68 14 0 – 0
Fax: +49 511 64 68 14 18
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