Jose Antonio Muñoz-Arteaga, Clara Villamil-Castañeda, Alma Laura-Dávila and Benjamín Hernández-Campuzano
Instituto Tecnológico de Estudios Superiores de Monterrey Cuernavaca Morelos
Narcolepsy is a chronic neurological disorder that causes irregular sleep-wake cycles, sleep attacks, muscle paralysis, excessive sleepiness during daytime, and hallucinations. It is a fairly uncommon condition, estimated to affect around 1 of 1200 people. It is not a long-term physically threatening condition by itself, but the loss of consciousness during activities such as walking down the stairs or driving could end up causing an accident, resulting in grave injuries and, in some cases, death
The causes for narcolepsy are still not fully understood; however, there is an apparent correlation between a specific variation of the HLA-DQB1 gene, the HLA-DQB106:02, with narcolepsy. Around 99.5% of people affected by narcolepsy, commonly paired up with cataplexy, possess this allele. It is also worth noting that this variation of the gene alone is not guaranteed to cause narcolepsy in a person, as the HLA-DQB106:02 allele is fairly common in the general population, but only a few of those with it develop the disease. This indicates that the development of narcolepsy, while strongly tied with the HLA-DQB1*06:02 gene, also requires other genetical and environmental factors for it to manifest. The genomic location of the HLA-DQB1 gene is shown in Figure 1.
Narcolepsy and Sleep Cycles
In a regular sleep cycle, a person enters the first three non-REM stages of sleeping in succession, number one being the closest to being awake and number three the deepest stage of sleep. These stages are defined by the progressive decrease in brain temperature, breathing rate, blood pressure, heartbeat rate and awareness of the surroundings. These three stages take about 60 to 90 minutes to go through, and after them, REM stage sleep is entered. REM stage sleep lasts for about 30 minutes, lasting longer during the last sleep cycles before waking up. It is characterized by significantly different behaviors of those of the first three stages, like rapid eye movement (hence the acronym REM), irregular and rapid breathing, heartbeat and blood pressure similar to those being awake, the occurrence of memorable dreams, and complete unresponsiveness from the muscle system. The paralysis of the muscles is a natural safety measure the brain takes during REM sleep in order to prevent the body to act out of dreams, which could result in physical injury. After REM sleep, the cycle starts again, with a little variation on the duration of each stage of the cycle.
People with narcolepsy, however, have completely irregular sleeping cycles. They often enter REM sleep around 15 minutes after they start sleeping, in between the first stages of sleep, and even during the day. They are prone to experience periods of full wakefulness during nighttime sleep, making uninterrupted rest difficult to achieve. People affected by this condition also often have hallucinations while falling asleep or while waking up, suffer from sleep paralysis, have realistic and unpleasant dreams and experience an episodic loss of muscle function triggered by strong emotions, known as cataplexy. While all of the above are symptoms a narcoleptic person can possess, it is rare for all of them to be present in the same person, the most common being cataplexy which is present in around 70% of all narcolepsy cases.
HLA-DQB1’s Function in the Human Leukocyte Antigen
The HLA (Human Leukocyte Antigen) is a gene group that codes for the proteins of the HLA complex, which is part of the immune system. Its main function is to make the distinction between the body’s own proteins from the foreign ones produced by viruses or bacteria.
The HLA is the human version of the MHC (Major Histocompatibility Complex), which is present in all vertebrates and helps in the recognition of foreign proteins in order to trigger the appropriate immune system’s response. Genes in this complex can be categorized into three basic groups, depending on their function.
The MHC class I genes in humans code for proteins which are present on the surface of almost every cell in the body. These proteins are bound to protein fragments exported from within the cell, so the T-cells can identify these peptides as foreign or own. In a healthy cell, the peptides exported from within the cell would all fall under the “own” category, while in an infected cell, some of the peptides would fall under the “foreign” category, causing the T-cells to trigger the cell’s apoptosis. The human genes in this class are the HLA-A, HLA-B, and HLA-C.
The MHC class II genes code for proteins exclusively present on the surface of specialized immune system cells, called antigen presenting cells, and have a similar function to the class I proteins, which is displaying peptides to other immune system cells. The HLA-DQB1 is part of this class, along with the HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DRA, and HLA-DRB1 genes.
The last class is the MHC class III genes, these ones have a somewhat different function, involved with inflammation and other immune system activities. They are not as specific as the previous two classes, and some of their functions are still unknown.
Materials and Methods
To further understand the interaction between the HLA-DQB1 gene and narcolepsy, we decided to look into the proteins associated with each of them. The HLA-DQB1 gene codes for one of the two chains composing the HLA-DQ protein, which is an MHC class II and is present in the surface of various antigen presenting cells. The HLA-DQ protein is a heterodimer, consisting of an ?-chain, coded by the HLA-DQA1 gene, and a ?-chain, coded by HLA-DQB1.
Next, we researched one of the most widely accepted narcolepsy causes, the loss of hypocretin-producing neurons on the hypothalamus. Hypocretin has two primary functions on the human body, maintaining alertness during long periods of time and participating in the arousal response. When there is hypocretin deficiency, sleep-wake cycles become irregular and unstable, which is one of the symptoms of narcolepsy.
In figure 2, we can see an HLA-DQ*0602 heterodimer protein in a peptidic bond with a hypocretin. For reasons still unknown, in the cases of people with narcolepsy, when the HLA-DQ protein presents the body’s own hypocretin to the T-cells, they do not recognize it as part of the body. Therefore, they attack the hypocretin-containing neurons, as if responding to an infection.
The 3D models of the HLA-DQ and Hypocretin proteins were obtained from the webpage “Protein Data Bank” (http://www.rcsb.org/structure/1UVQ)
In the “STRING” database (https://string-db.org/cgi/network.pl?taskId=Dxkhe4Zk8IKn), we obtained a variety of genes related to the HLA-DQB1 gene, this allowed us to identify other possible genetic factors involved in the development of narcolepsy. The results of this investigation can be seen on figure 3.
In order to obtain information about the HLA-DQB1 gene, we consulted the “GeneCards” database (http://www.genecards.org/cgi-bin/carddisp.pl?gene=HLA-DQB1#diseases) This allowed us to better understand the function of said gene, and combining it with the information obtained from this article from the United States’ National Library of Medicine (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3589707/), it was possible to make the relationship between the two.
We obtained information about Narcolepsy from various reliable websites, including the United Kingdom’s National Health Service database (https://www.nhs.uk/conditions/narcolepsy/), the United States’ National Library of Medicine (https://ghr.nlm.nih.gov/condition/narcolepsy#genes), as well as the National Institute of Neurological Disorders and Stroke (https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Narcolepsy-Fact-Sheet#3201_5). All of them were used to identify and understand the effects and causes of Narcolepsy.
Results and Discussion
By gathering the already available information on both the Narcolepsy disease and the functions associated with the HLA-DQB1 gene, we concluded that there was indeed a tangible correlation between the two. For reasons still unknown, the gene variety HLA-DQB10602 pointed out an important predisposition on developing Narcolepsy, as well as Cataplexy. When the appropriate environmental and genetic factors occur, the HLA-DQ0602 proteins present the Hypocretin to the T-cells, which do not recognize the Hypocretin as part of the body. This triggers the apoptosis of the Hypocretin-containing neurons at the hypothalamus, which then results in a severe deficiency of Hypocretin, giving birth to the irregular sleep-wake cycles characteristic of narcolepsy. Without regular sleep patterns, the amount of REM sleep that the individual has would be imbalanced, leading to another of the odd symptoms present in narcolepsy, entering REM sleep as soon as 15 minutes after starting to sleep as a result of the body trying to compensate for the lack of REM sleeping in these irregular cycles. The combination of all the previous sleeping problems could then produce one of the other known Narcolepsy symptoms, sleep paralysis, because of the REM stage sleep not functioning properly and blocking the muscle response while awake. Hallucinations could also be explained in this way, since REM sleep is when we usually dream, so the depravation or malfunction of this sleep stage could lead the brain to experience dreams when our wakefulness is fading or before waking up entirely.
Knowing all of this, many questions about Narcolepsy’s precise cause still remain. What are the genetic and environmental factors needed in order for this condition to develop? We think one possible answer to this question lies in some of the genes that are closely related to the HLA-DQB1. Maybe when combined with a certain allele of the HLA-DQA1 gene, the resulting heterodimer has the adverse effect of marking the Hypocretin as a foreign substance. If this was the case, that would explain why the vast majority of people that possess the HLA-DQB1 variant do not develop Narcolepsy, because it would also require them to have a specific variant of the HLA-DQA1 gene as well. We believe this is one of the most probable genetic factors required for Narcolepsy to develop.
In the environmental factors, there has already been research that has discovered that people who suffered from a streptococcus infection in childhood and possess the HLA-DQB10602 gene variant had five times more possibilities of developing Narcolepsy, while other kinds of children’s infectious diseases had little or no effect in the probability. There is still not a definite answer on why this kind of particular disease augments the probabilities of developing Narcolepsy at such high levels, but we believe a plausible explanation for this effect is that once the streptococcus infection has been fought, some of the developed antibodies remain. When the Hypocretin is presented to any of these antibodies, the HLA-DQ0602 makes it appear like something foreign to the T-cells, which respond by killing the Hypocretin-containing neurons in the hypothalamus.
We do not have the evidence to claim any of these theories as true, but that is exactly what is the most intriguing about this condition. It appears to be the combination of many very specific genetic and environmental factors, that together cause this peculiar autoimmune system reaction. Understanding not only Narcolepsy but many other kinds of diseases that have a base in genetics is essential to go further into medicine’s next step: genetic manipulation to suppress or alter problematic genes and eliminate this kind of diseases from the root itself.
The definite cause of Narcolepsy is still unknown, but we believe that in a not-so-distant future, scientists will have a better understanding of both genetic diseases and their manipulation. For now, we need to focus on researching and discovering the genetic and environmental factors that ultimately lead to the development of Narcolepsy. There are already several investigations pointing out different directions and possibilities, but scientists will not know the reason for sure until they explore and experiment around these theories. The answer to this and many other genetic-related diseases are out there, but we have not been able to reach them just yet. It is of utmost importance to keep striving to reach these answers.
|HLA||Human Leukocyte System|
|MHC||Major Histocompatibility Complex|
|REM||Rapid Eye Movement|
Narcolepsy, HLA-DQB1, Genetic Diseases; Genetic Predisposition
The authors, José Antonio Muñoz-Arteaga and Clara Villamil-Castañeda, would like to thank our science mentor, Dr. Benjamín Hernández-Campusano, for all the help he has given us during the development of this article. We would also like to give recognition to the work of the authors we have read, because thanks to all of them, we were able to develop this article and have a better understanding of this disease, as well as its relationship with genetics.
Longstreth, W. T., et al (2009). Narcolepsy and Streptococcal Infections. Sleep, 32(12), 1548.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2786037/
Siebold, C. et al. (2004-02-05). 1UVQ. From Biological Macromolecular Structures Enabling Breakthroughs in Research and Education. Web site: http://www.rcsb.org/structure/1UVQ
(2017). From STRING. Web site: https://string-db.org/cgi/network.pl?taskId=Dxkhe4Zk8IKn
(2018). HLA-DQB1 Gene. From GeneCards. Web site: http://www.genecards.org/cgi-bin/carddisp.pl?gene=HLA-DQB1#diseases
Ayumu Inutsuka, et al. (2013). The physiological role of orexin/hypocretin neurons in the regulation of sleep/wakefulness and neuroendocrine functions. From National Center for Biotechnology Information. Web site: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3589707/
(2018). Narcolepsy. From National Health Service. Web site: https://www.nhs.uk/conditions/narcolepsy/
(2018). Narcolepsy. From National Library of Medicine. Web site: https://ghr.nlm.nih.gov/condition/narcolepsy#genes
(2018). Narcolepsy Fact Sheet. From National Institutes of Health. Web site: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Narcolepsy-Fact-Sheet#3201_5