Mechanisms Underlying Rett Syndrome
By: Nathalie Cardenas Zelaya



Rett’s Syndrome is a X-linked dominant neuro-developmental disease that mostly affects females (Psoni,2011). It has an occurrence of 1 in 1-20,000 live female births (Armstrong,2005). It is the second most frequent source of severe mental retardation in females (Temudo,2010). Usually the patients affected are small girls with lost speech patterns and abnormal hand use, along with the occurrence of stereotopies and ataxia (Armstrong,2005). Stereotopies are abnormal repetitive meaningless movements that are most often seen in childhood (Jankovic, 1994). Cognitive aspects of the disorder include abnormal breathing, heart rate, peripheral circulation, and emotional hyper excitability which have already been defined differently from autonomic dysfunction and seizures (Armstrong, 2005).


Symptoms include normal early development followed by psychomotor regression and beginning of microcephaly (abnormally small head circumference).It also includes variations of mental retardation (Psoni,2011). In terms of neurological chemical abnormalities, patients with Rett syndrome have dysfunction in their acetylcholine, serotonin, and glutamate systems. Also affected in these patients are substance P and new nerve growth factor (Armstrong, 2005). Anatomically, the brain weight of a Rett syndrome carrier is typically less than a non-Rett syndrome control for similar age and height. This implies that Rett syndrome is a disease of the nervous system along with the fact that MeCP2 are mostly expressed in the neurons (Armstrong, 2005). Futhermore, there is a significant decrease in dendritic territories in Rett syndrome of the motor, front and subicular cortices when compared with non Rett syndrome cases. In addition the symptoms of breathing irregularities, heart rate variability, tiny cold feet, and difficulties swallowing suggest autonomic impairments (Armstrong, 2005).

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Rett’s syndrome has also been associated with methyl-CpB-binding transcriptional repressor, MECP2 (Yusufzai,2000). MeCP2 is a nuclear protein (Cohen, 2011). Possible causes of the syndrome’s occurrence might be due to several mutations in the MeCP2. MeCP2's function is to bind to methylated CpGdinucleotides. Any missense or nonsense mutations found in MeCP2 abrogate methylation specific binding to the DNA template. This loss of specificity can lead to target genes not being repressed by MeCP2 mutant. MeCP2 may in turn have a greater tendency to bind unmethylated sequences in a non-ordered fashion, causes alteration in normal gene expression (Yusufzai, 2000).

Another way associated with the cause of Rett Syndrome is through phosphorylation in the S421 location of the MeCP2 gene in reaction to neuronal activation. This leads to defects in synapse development and behavior (Cohen, 2011). Similar another possible cause is X chromosome inactivation. Mutations within the MeCP2 gene located on chromosome Xq28 are found in about 80% of all typical Rett Syndrome cases. Therefore, depending on which of the chromosome are inactivated, an assortment outline of healthy wild type allele expressing and affected (mutant allele expressing) cells will be made. Patients with Rett syndrome are frequently chimeric for the wild type and mutant MECP2 (Jost, 2011).


In terms ofdiagnosis, even though MeCP2 is associated with Rett syndrome, it is clinical observations which define Rett Syndrome rather than the genetic component (Psoni, 2011). Five of the following are types of Rett syndromes identified 1) neonatal type accompanied with seisures , 2) congenital type c) the "forme fruste", 3) the preserved speech variant or Zapella variant and finally the 4) the late regression form (Psoni, 2011). It used to be believed that MeCP2 mutations in males would be considered fatal but it was now found those MeCP2 mutations in males leads to the following 1) severe neonatal encephalopathy, 2) RTT-like features due to somatic mosaicism and 3) non-specific, non progressive mental retardation. Regarding the genetic component of the disease, in a study done by Psoni, 2011, researchers conducted a molecular analysis of Greek female patients with Rett Syndrome. In this study, the common Rett syndrome mutation, accounted for approximately 54 percent of the alternations revealed. Females carrying the altered MeCP2 gene had more severe issues with terms of spasticity, tremor and ataxia, decelerated head growth and hand use. This study was interesting in the fact that it combined clinical observations with genetic components by using hand function as an index of for truncated mutations (Psoni, 2011). The more severe the impairment of the hand movement combined with earlier onset of stereotypies was associated with classic RTT MeCP2-positive when compared to the variant forms of RTT MeCP2-positive patients. Another symptom associated with earlier truncated mutations was respiratory dysfunction (Psoni, 2011).

Animal Models


Rett syndrome has been investigated using several different animal models. These include drosophila and mouse models. Mice models are a more popular choice for studying Rett syndrome because Drosophila lack an ortholog of the human MeCP2 (Vonhoff,2012). Despite this setback, Drosophila models can be used to identity genetic targets and cellular consequences of MeCP2 gain of function mutations in neurons (Vonhoff, 2012). Therefore, using Drosophila models can be used because though classic Rett syndrome in humans is caused by a loss of the MeCP2 gene, gain of function of MeCP2 in flies can also cause mental abnormalities. Specifically, the outcome of a gain-of-function of MeCP2 in Drosophila is developmental deficiency and motor short-comings of which are similar enough to RTT symptoms (Vonhoff, 2012). In a study done by Vonhoff et al (2012), dendritic defects but normal membrane properties resulted from MeCP2 expression Drosophila motor-neurons. This suggests that drosophila models can be used to investigate certain areas of MeCP2 function in neurons, since dendritic defects have previously been associated with Rett syndrome.

Mice Model

A second animal model is the mouse model. This model is a more ideal than drosophila as previously mentioned. In a study by McGraw et al (2011), asked the question if neurological function could be protected following later absences of the MeCP2 gene if the nervous system established a functional epigenetic program during the early stages of life. In order to answer this question, researchers developed an adult model of RTT by crossing mice containing a floxed MeCP2 allele with a tamoxifen-inducible CreER allele in order to erase MeCP2 when the mice is fully adult (eg post natal = 60 days). In other words, MeCP2 expression was deleted only during adult life (McGraw, 2011). The results of the study showed that mice without MeCP2 (AKO) only as adults began to display symptoms of Rett syndrome and behavioral deficits similar to the germ-line null mice. AKO mice had decreased activity, had abnormal walking patterns, and developed rubbing paw motions, all of which were not unlike the knock-out mice. Finally, in the end, both the AKO and knock - mice died prematurely with comparable median time to death. This study suggested that association of the disease as a “neuro-development” disorder or stage-limited function of MeCP2 may not be true, at least in terms of mouse models. The results of this study strongly suggest that there is dependence of the mature brain on MeCP2 function otherwise the results would have shown the AKO mice having at least some sort of protection against the disease which they did not.
Furthermore, in third animal model is another mouse model study done by Zhang et al (2011), researchers investigated breathing instability of Rett syndrome patients by testing the hypothesis that central Co2 chemo receptors are disrupted. They did so by studying Co2 chemo sensitivity in mice model of RTT. Supported by evidence from in vivo observations, in vitro studies in brain slices suggests that Co2 chemo sensitivity of the locus coeruleus neurons were impaired in MeCP2-null mice. The MeCP2-null mice’s Kir channels were screened with real time PCR, which indicates that the over-expression of Kir4.1in the locus coeruleus areas. In a heterologous expression system, an overexpression of Kir4.1 resulted in a decrease in the ph sensitivity of the heteromeric Kir4.1- Kir5.1 channels. Since Kir4.1 nd Kir5.1 subunits are also found in the brain stem of breathing- related regions, the Kir4.1 over expression may not allow C02 to be sensed until hypercapnia reaches a critical level, resulting in periodical hyper- and hypo- ventilation in MeCP2-null mice. This study suggests perhaps the same conditions can be applied to people with RTT.

Possible Treatments

Possible treatments for Rett syndrome was explored in a study done by McCauley et al (2011) in which they tested the hypothesis that deaths in RTT patients might be caused by cardiac abnormalities. 379 RTT individuals’ electrocardiograms were taken, and it was showed that 18.5% had prolonged corrected QT interval (QTc), an indication that this dysfunction can increase the chances of developing an unstable fatal cardiac rhythm. Male mice lacking MeCP2 function also contained elongated QTc and display increased vulnerability to induced ventricular tachycardia. Futhermore, female heterozygous null mice show an age-dependent extension of QTc correlated with ventricular tachycardia and cardiac-related death. This implies that if a null female shared similar traits as RTT individuals, perhaps there is a correlation between mutations in the MeCp2 gene and cardiac related deaths.

Genomic Wide Activity-Dependent MeCP2 Phoshorylation

A recent and critical paper of importance on the topic of Rett syndrome is a study done by Cohen et al (2011) on genomic wide activity-dependent MeCP2 phoshorylation which controls neuron development and function. This paper explores the idea that RTT is caused by mutations in the MeCP2 gene. Neuronal activation causes MeCP2 to become phosphorylated at a serine residue 421 in the brain. This paper wanted to test the hypothesis that if there is a disturbance in vivo in the meCP2 S421phosphorylation, the result is that there is damage during synaptic development. This hypothesis was tested through the use of knockin mice in which S421 of MeCP2 was altered into an alanine. First, the researchers used Western blotting and immohistochemistry to ensure that MeCP2 S421phosphorylation was eliminated in these knockin. Recent evidence showed that MeCP2 can be expressed in both neuronal and glial cells in the mouse nervous system. Secondly, the researchers used immunocytochemistry in cultured neurons to determine if MeCP2 levels in neurons are disturbed by the S421A mutation. After analysis of both the knockin and the wild type, results showed that MeCP2 S421A mutations do not change the levels of MeCP2 protein expression in the brain. Thirdly, when staining with anti-MeCP2 antibodies in neurons from both the knockin and the wild type mice, it was shown that mutation of MeCP2 S421does not alter the underlying spreading of MeCP2 in the nucleus and that MeCP2 S421 phosphorylation might not be required for targeting of MeCP2 to chromatin. In fact, the study showed that neuronal activity-induced phosphorylation of S421is spread consistently allocated across MeCP2 molecules in the genome. This means that if, a single MeCP2 molecule is bound every two nucleosomes and phosphorylation is evenly distributed, then an independent event has occurred every 900-300 bp. Therefore, pS421 MeCP2 is very likely to be found throughout the genome, and has the prospect of altering the chromatin at the level of the genome. The conclusion is that phoshorylation of MeCP2 does not just regulate certain genes. Instead, when MeCP2 is phosphorylated, it functions as a histone like factor that might cause a genome-wide response of the chromatin to neuronal activity during nervous system development. The final result of this paper was to suggest that perhaps Rett syndrome might occur due to loss of chromatin remodeling. Futher studies that look at the link between phosphorylation of MeCP2 and Rett syndrome could be the use of other additional knockin mice to alter the function of activity-dependent function of MeCP2.


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