Imagine that for some people, over-the-top happiness and excitability can be symptoms of a debilitating disorder with wide-ranging implications: Angelman syndrome. Resulting from the deletion of three nucleotides in chromosome 15 in somatic cells, Angelman syndrome can lead to a variety of disabilities, from delayed development to intellectual disabilities and even seizures.
The basic principles of genetics state that certain genes are correlated with certain traits - that the only way to change the phenotype or the expression of a trait is to directly alter the sequence of nucleotides. However, the concept of epigenetics rules that that isn’t always the case. In fact, reversible, chemical modifications or additions to the DNA can actually dictate the phenotype.
For example, when a compound, such as a methyl group (CH3), is incorporated into a region of the DNA, it has the ability to prevent transcription, ensuring that certain genes cannot become proteins. This phenomenon was put to the test when scientists experimented on overweight yellow mice. When comparing these abnormal yellow mutants to the regular mice with agouti fur, scientists found that if they fed a diet of methyl-containing compounds to the mother, her children would have agouti fur in comparison to the mothers who were not fed the methyl rich diet.
Genomic imprinting is an example of such a phenomenon. For many years, scientists have adhered to Mendellian principles. When scientists crossed purple and white plants together, they did not differentiate between the maternal and paternal traits.
That all changed with the idea of genomic imprinting. Genomic imprinting states that whether or not the mother or the father passed down a specific gene affects how the trait will be expressed. Occurring during gamete formation, genomic imprinting is responsible for silencing a particular allele of a gene. Different alleles are silenced depending on whether or not they are found in a sperm cell or an egg cell.
For example, in an egg cell, the allele, UBE3A, which is in charge of protein degradation in brain cells, is expressed, while the other alleles, SNRPN and NDN, which supervise pre-mRNA splicing and neuron growth respectively, are silenced. In comparison, in a sperm cell, SNRPN and NDN are expressed while UBE3A is silenced. When the sperm and egg cells unite to form a zygote, the zygote contains one working copy of each of the alleles from the mother and the father.
Angelman syndrome is a consequence of when genomic imprinting fails to function properly. Instead of the egg cell providing a working copy of UBE3A, all of its alleles, the silenced SNRPN and NDN and the working UBE3A, are deleted. Thus, the zygote resulting from the pairing between the egg cell and the sperm cell will lack a working copy of UBE3A, thus leading to an inability to degrade proteins in the brain cells.
Protein degradation in the brain is crucial to it being able to grow and function normally. It can enhance plasticity of the brain, allowing the brain to adapt to new circumstances with more efficient synaptic connections. A lack of this ability has numerous consequences on the health and wellbeing of a person. Children as young as 6 months of age can experience numerous developmental delays, such as not crawling or babbling. Other problems include stiff movements, difficulty feeding, small head size, trouble sleeping, scoliosis, and abnormally excitable personalities.
Unfortunately, no treatment currently exists for this disorder. Instead, prevention is more emphasized than treatment with doctors trying to resolve the sleep, medical, and developmental issues instead. However, there are more and more advancements in the medical world in terms of treating diseases that were previously thought to be incurable. In fact, Mark Zylka, PhD, Director of the UNC Neuroscience Center, discussed how his research was able to show that Angelman syndrome can be treated with gene editing through CRISPR-Cas9. Already, there have been breakthroughs in the case, and perhaps in the future, Angelman syndrome patients can look forward to a wide array of treatments.
Mackenzie Chen is a 1st Year student at the University of Virginia.