UBE3A: how Epigenetics can Determine the Nature of a Disease
Most readers probably learned it in school: we carry two copies of every gene in us. Mutations in these genes can cause disease. We call it a recessive mutation if such a variant has to be inherited from mother and father, i.e. both copies of the gene in the child must be affected for a disease to manifest. For a dominant variant, on the other hand, it is sufficient if either the mother or the father inherits such a copy, because a single copy of this variant triggers the disease. An example of a devastating mutation with dominant inheritance is Huntigton’s chorea. This degenerative disease, which is unfortunately fatal without exception, is passed on to the child from an affected parent with a 50% probability. It does not matter whether the variant was inherited from the mother or the father for the course of the disease, because on the so-called autosomes (these are all chromosomes except the sex chromosomes X and Y), both copies of the DNA segments are actually equivalent. But is that really always true? Not quite! And that is one of many reasons why the subject of epigenetics is currently so popular.
Sections of chromosomes can be inactivated, a few even specifically on the maternal or paternal copy
Chromosomes are chemically highly complex three-dimensional structures. A chromosome consists of double strands of DNA that are wrapped around certain supporting proteins and twisted several times, like an old telephone cable (see picture on the left). As astonishingly stable as these structures are, they are unfortunately not indestructible. Certain places seem to be more susceptible when it comes to the occurrence of breaks or deletions (sections that fall out and are therefore missing as a result). A comparatively common deletion affects the long arm of chromosome 15 between bands 11 and 13 (15q11-q13). Children who inherit this deletion are impaired in their development.
So far everything is just like it is for other chromosome irregularities. In contrast to other deletions, which can trigger serious diseases, for the 15q11-13 deletion it matters whether this deletion was inherited from the mother or the father. If this deletion has occurred on the maternal copy, affected children usually show symptoms of Angelman’s syndrome by around one year of age. If a child receives a paternal copy of chromosome 15 with this deletion, the symptoms of Prader-Willi syndrome usually become apparent at a somewhat later age.
What are the reasons for this unusual inheritance characteristic? Well, the area q11-q13 on chromosome 15 is subject to a process called genomic imprinting. We should by no means imagine our genome as something rigid; it is not just a stored text that is invariably present in our cell nuclei. Over the course of the specialization a cell undergoes during embryonic development, most areas of the genome are shut down. A cell in our skin or our brain, for example, shouldn’t read the insulin gene, which is why the corresponding section of the DNA is chemically modified so that it becomes inactive. And that is exactly what happens in some places in the genome specifically for the maternal or paternal copy.
Which genes are in section 15q11-13?
We can only speculate about the “reason” for this gender-specific shutdown of gene variants, which I will not even begin in this article. Let’s rather take a look at the genes that are on section 15q11-13 and that are subject to imprinting: there we have, for example, Necdin and SNRPN (small nuclear ribonucleoprotein polypeptide N). For these two genes, it is always the maternal copy which is shut down in our cells; only the paternal copy is active. If the paternal copies of these genes are missing due to the deletion, then in this case the maternal copy cannot compensate for the loss of function. The loss of function of these two genes then probably contributes significantly to the symptoms of Prader-Willi syndrome.
Of a third gene located in this section, UBE3A (ubiquitin-protein ligase E3A), both copies are active in most of our cells. In the nerve cells of our brain, however, the paternal copy is shut down, so that only the maternal copy remains active. If this maternal copy is missing, as in Angelman syndrome patients with maternal 15q11-q13 deletion, the function of UBE3A thus is also missing.
UBE3A is a ubiquitin ligase, which means that it attaches small markings (ubiquitin) to proteins that are intended for degradation. A ubiquitin ligase is a sort of sorting device; because when a protein bears such markings, it literally goes into the bin. In this case, the bin refers to the proteasome, a hollow cylindrical complex in the cell in which proteins that are no longer used are broken down into their components in order to build new proteins from them. If this sorting does not work properly, the entire cell metabolism is disturbed. Old, no longer properly functioning proteins accumulate and ultimately become toxic for the nerve cells. Exactly which proteins these are is the subject of current research. It is hoped that this will help to better understand the disease mechanism in order to better counteract the consequences of the UBE3A loss of function.
Modern therapies rely on reactivating the paternal copy of UBE3A [UPDATE from February 2021]
Approaches to reverse the deactivation of the intact paternal copy, i.e. reactivate the gene, are still in their infancy. It makes sense to try to inhibit the function of LNCAT in order to disrupt the continuous shutdown of the paternal UBE3A. This is exactly what the companies GeneTx and Ultragenix are trying to achieve with so-called antisense oligonucleotides. GTX-102 is such an oligonucleotide that it is complementary to the section of LNCAT on which the opposite strand of UBE3A is encoded. Preclinical studies have confirmed that GTX-102 is able to inhibit the silence of the paternal UBE3A and reactivate protein expression from the paternal UBE3A gene. A first clinical study from 2020 then showed that several symptoms of Angelman’s syndrome improved after treatment with GTX-102. However, some patients also showed muscle weakness after high doses. Even if this muscle weakness occurred only temporarily and was completely reversible, the causes now need to be investigated. So the field of targeted therapies for rare genetic diseases remains exciting.