Decoding Rett syndrome: New pieces to the puzzle
Rett Syndrome is a neurological disorder that affects about 1 in 10,000 girls. Back in 1992, University of Edinburgh researcher Adrian Bird discovered that the protein, MeCP2, plays a major role in the disease. The story of MeCP2 is in many ways a microcosm of human genetics. It has become the showcase gene for many complex epi-genetic phenomena including X-linked inactivation, DNA methylation, and genomic imprinting. These gender-specific bargaining chips provide compatibility in an evolutionary system where sex-chromosome provisioning is inherently assymetric. In two new papers, one in Nature and the the other in Nature Neuroscience, Bird and collaborator Michael Greenberg, show how mutations found in Rett Syndrome affect the interaction of MeCP2 with a key regulatory protein known as NCoR.
Nearly all cases of Rett Syndrome are caused by mutations at various postions in the MeCP2 gene. Bird and Greenberg analyzed the locations of these mutations using the RettBase MeCp2 database, and found they cluster to two primary locations—the well-known methyl-CpG binding domain, and a new hotspot within a transcriptional repressor domain (TRD). When they compared these locations with mutations found in the general population by using the Exome Variant Server, they found no overlap. This suggests the that the MeCP2 and TRD regions are the primary regions involved in Rett’s.
The researchers hypothesized that the newly found TRD region must act through a unknown regulator of MeCP2 function. Using mass spectrometry, they were able to identify several factors which they had purified from Mecp2-EGFP “knock-in” mice. Most of these factors turned out to be subunits of the co-repressor, NCoR, which was previously known to interact with MeCP2. This is the first identified example of a protein-protein interaction known to be disrupted in Rett’s.
In the Nature paper, the researchers further report that activity-dependent phosphorylation of MeCP2 mediates its interaction with NCoR. They used a technique known as phosphotryptic mapping to identify three sites that are directly phosphorylated in MeCP2 as a result of elevation in cAMP or BDNF. More generally, they showed that membrane depolarization, and therefore activity, results in the phosporylation.
One confounding factor in trying to pinpoint the mechanisms underlying Rett Syndrome is that both loss of MeCP2, and overexpression of MeCP2, can lead to the disease. In mouse models of the disease, this could be accounted for by the observation that both loss of NCoR binding, and constitutive binding of NCoR can lead to disease symptoms. While not a complete explanation of the role of MeCP2 in the disease, it provides some clues to help dissect the involvement of the many different kinds of mutations involved.
Despite the rarity of Rett’s syndrome, its impact on our understanding of human genetics and neural development should not be underestimated. As one of the autistic spectrum disorders, research on Rett’s helps connect molecular mechanics to behavior. For example, when MeCP2 is bound to DNA it can cause condensation of the chromatin structure, and also form complexes with histone deacetylaces. In demostrating that neural activity, and subsequent signal tranduction pathways, lead to modifications of MeCP2, the researchers have revealed a path from the environment directly to the genes.
The X-linked inactivation of one copy of the MeCP2 gene in females adds another layer of complexity to the disease. The celluar mosiac formed by the pattern of inactivation, particularly in the brain, needs more study to be undersatood. The fact that Rett’s symptoms can be “rescued” in mice by the expression of MeCP2 in postmitotic neurons is encouraging. In humans, Rett’s is frequently not observed untill the first or second year of life. As MeCP2 activation correlates with this period of rapid neural maturation, Rett’s is generally considered to be neurodevelopmental disease, as opposed to a neurodegenerative disease.
Rett’s is hardly ever observed in males for the simple reason that they fail to thrive long before birth. In those rare cases that a presumably XXY male child is rescued by the additional X chromsome, as in Klinefelder’s disease, rare opportunity to study the disease etiology is afforded. The efforts of these researchers, and the larger Rett’s community, together with the insights afforded by massive data collation have turned a rare disease into a primary source of knowledge about how evolution proceeds through the interplay of the sexes at the genetic and epigenetic levels.
Beck - Tropicalia
I know, traditionally the words “desert island” in this context mean what song would you take with you to a desert island but seriously, one song? One? Think about it. One song to listen to forever. The same song. Over and over.
That’s a tough one. At first I thought, well, I have quiet a few favorite songs. And maybe I wouldn’t have to listen to a song all the time, just have it with me (and play it on what? I don’t think there is electricity on deserted islands). I guess I could always just turn off the music an do something else, like whittle statues of Japanese monsters out of wood or make invisible friends. Then again, if I’m whittling, I could make a flute out of some balsa wood and make your my music. By the time they rescue me, I’d have a whole repertoire of songs laid out and I’d be the next Zamfir. Imagine that – when they have the press conference announcing my rescue (WOMAN FOUND AFTER 28 WEEKS ON DESERT ISLAND, LIVED OFF NUTS AND BERRIES WHILE PRAYING TO A WOODEN STATUE OF MOTHRA) I could whip out my homemade flute and get myself a book deal and a recording contract at the same time.
Anyway, this song. I decided not to go with a desert island song in the above context but with a song that makes me feel like I’m on a tropical island. It’s the kind of song that makes you want to dance in the sand with someone you love, twirling each other around while the sun sets and then you walk hand in hand back to some decorative gazebo where you will continue dancing while drinking exotic cocktails with umbrellas in them and later, on your way back to your beach house where you intend to have sex until dawn (but you fall asleep at about 1am because those drinks were kind of potent), you pass by a young woman who is playing a wooden panflute next to a sign that says “Church of Mothra and Zamfir, donations accepted.”
L4D: Special Infected
- Smoker Mutations may occur to someone who is/was a heavy smoker. Higher levels of cancer or tar in the victim’s lungs could inhibit complete exhalation and fill the respiratory track with “smoke.” Higher concentrations of the “smoke” in the body may facilitate further mutations. There also could be a reaction to a fungus strain, given the smoky cloud of greenish-brown spores the Smoker gives off. The massive lumps on a Smoker’s body could be full of these spores, which release a cloud of smoke upon death.
- Hunter Mutations may occur due to interactions with elevated levels of lactic acid in the muscles and bloodstream—a result of heavy exercise (presumably from a continuous exercise-heavy lifestyle, such as parkour; fleeing from an Infected Horde is rather heavy exercise, but this alone would produce a large number of Hunters).
- Jockey Mutations may have resulted from someone who was confined to a wheel chair. The obvious regenerative properties (mutations and growths) of the Infection could indicate a restoration of spinal cord function, giving the infected person the ability to walk again. This would explain the hunchback appearance and the emotional mania. A separate speculation suggests that the Jockey’s mutations may be comparable to the Hunter’s, paired with some form of dementia that either was already present or developed as a result of viral brain damage.
- Tank Mutations are possibly related to body building supplements. Abnormally high levels of Creatine, Human Growth Hormone, and anabolic steroids (possibly produced naturally from some damage by the infection) could interact with the virus to promote tumor-like growth of muscle cells. If left uncontrolled, muscle mass would increase exponentially to the point where complex muscle movements are lost or limited and only basic movements (shuffling, climbing, thrashing, slow throwing, etc.) are possible.
- Charger Mutations are similar to the Tank and could mean that the Charger is a hybrid version of the Tank. Some steroids are used as an anti-inflammatory remedy for a rash or growth on one side of the body. An abnormal interaction with a localized and smaller concentration of steroids could have created the Charger. It might also be a reaction similar to gigantism (where excessive amounts of growth hormone is released, resulting in thickened bones and asymmetrical body structures), given that the Charger’s facial features and overall body shape is similar to that of someone with gigantism.
- Boomer Mutations probably relate to abnormally-high levels of fatty tissue or cholesterol in the bloodstream, which would also explain the large amounts of bile they produce. Bile is created to aid in the breakdown of lipids (fat). The human body’s natural bile production would have been assimilated as part of the Infection’s mutation. This would explain why, when Boomers burst, their torsos appear to be largely hollow. The space previously occupied by fatty tissue had been broken down and converted into a single, enormous sac for containing and producing bile.
- Spitter Mutations may have resulted in infecting a human subject with a helicobacter pylori infection (bacterial ulcer). Cells previously infected by the bacterial agent may have been consumed by the virus and caused it to mutate. Another take suggests that the mutations might be similar to the Boomer, except the hormone gastrin (responsible for making stomach acid) is hijacked, resulting in Spitters being able to create large amounts of acid. The Spitter’s sagging skin and awkward walk may be caused by the acid leaking into other bodily cavities and breaking down tissues.
- Witch Mutations seem related to an abnormal mental state which could indicate a predisposed mental disorder, like Autism, ADHD, Serotonin imbalance in the brain, etc. Neurotransmitter imbalances are theorized to be a cause of Clinical Depression. Psychological trauma could also be a factor, such as with the “bride Witch”, who may have suffered the mental stress needed to become a Witch when the Infected attacked her wedding. Since the Witch is one of the most notable gender-linked examples of the Special Infected, it is likely that there is also some sort of influence from female sex hormones. It might also be a reaction for anorexia, as all Witches are thin women, and attracted by sugar smell possibly due to lack of carbohydrates.