Mutations in the X-linked methyl-CpG-binding protein 2 (MeCP2), a transcriptional repressor, cause Rett syndrome and a variety of related neurodevelopmental disorders. The vast majority of mutations associated with human disease are loss-of-function mutations, but precisely what aspect of MeCP2 function is responsible for these phenotypes remains unknown. We overexpressed wildtype human protein in transgenic mice using a large genomic clone containing the entire human MECP2 locus. Detailed neurobehavioral and electrophysiological studies in transgenic line MeCP2(Tg1), which expresses MeCP2 at approximately two fold wild-type levels, demonstrated onset of phenotypes around ten weeks of age. Surprisingly, these mice displayed enhanced motor and contextual learning and enhanced synaptic plasticity in the hippocampus. After twenty weeks of age, however, these mice developed seizures, became hypoactive, and approximately 30% of them died by one year of age. These data demonstrate that MeCP2's levels must be tightly regulated in vivo, and that even mild overexpression of this protein is detrimental. Furthermore, these results support the possibility that duplications or gain-of-function mutations in MECP2 might underlie some cases of X-linked delayed-onset neurobehavioral disorders.

The vast majority of Rett Syndrome cases are due to mutations in the MECP2 gene. The MECP2 gene makes the MeCP2 protein. It is believed that mutations in the MECP2 gene cause "loss of function" mutations in the MeCP2 protein, meaning the protein cannot do its job. Researchers hypothesize that since the role of MECP2 is to shut down other genes the symptoms of Rett Syndrome are due to the effects of having genes "turned on" that should be "off".

One possible treatment option for Rett Syndrome patients is to restore, through gene therapy, appropriate levels of MeCP2. Before such studies can be undertaken it is imperative to know if too much MeCP2 is detrimental. Dr. Zoghbi and colleagues created mice which expresse twice as much MeCP2 protein as normal. Interestingly, the mice, early on, performed better then their typical counterparts in both cognitive and physical realms. However by 20 weeks the mice displayed seizures, spasticity and reduced movement. Many mice died prematurely.

These experiments clearly show that too much MeCP2 is detrimental. This issue will have to be taken into careful consideration for any potential treatments that attempt to increase levels of MeCP2 protein. The paper also points out that there have been a few published cases of individuals with Rett that have increased levels of MeCP2 protein. These individuals did not present as classic Rett but rather with preserved speech variant, autism or Pervasive Developmental Delay. It is conceivable that in these individuals their particular MECP2 mutation led to a "gain of function" scenario. The mutation, rather then simply rendering the protein ineffectivce ("loss of function") perhaps caused the protein to gain a novel and detrimental function.

This paper adds an important piece of data to the Rett research field.

Regulation of gene expression is critical to the proper development of neuronal cells. The methyl-CpG binding protein 2 (MeCP2) operates as a transcriptional repressor by facilitating histone deacetylation and DNA methylation-dependent transcriptional silencing. This study examined the importance of MeCP2 in the regulation of neurite formation in PC12 cells. Expression of MeCP2 increased in a time-dependent manner after induction of neuronal differentiation. Expression was assessed at both the transcriptional and translation levels, and reached a maximum at 24 h post-induction. In addition, a marked inhibition of neurite extension and proper localization of a marker for synapse formation, synapsin I, were observed when MeCP2 expression was decreased by the addition of an antisense morpholino oligomer directed to the translational initiation site for MeCP2beta. The removal of the antisense oligomer allowed neurite extension to progress. However, the addition of antisense oligomer to previously differentiated PC12 cells did not affect established neurite processes. Taken collectively, our results indicate a role for MeCP2beta early in the events of neurite formation and that the relative levels of MeCP2alpha and MeCP2beta may be different in early differentiating neurons than is found in the adult brain. In addition, unique functions may exist for the two isoforms of MeCP2. Our results indicate that the inhibition of neurite elaboration caused by a reduction in MeCP2 may be reversible.

In March of 2004 the Bird lab and the Minassian lab announced the discovery of a new form of MeCP2. The new protein, which is slightly longer then the original form, is 10 times more abundant in the brain. Dr. Oxford and colleagues designed experiments to elucidate the different functions of these two forms of MeCP2. The researchers found that the original protein seems to have an important role in the immature neuron, whereas the new protein seems to play a crucial role just before maturation is achieved and thereafter.

RSRF is funding the creation of knockout animal models specifically for the new isoform. This project should elucidate further the role of the new protein. For more information please visit www.rsrf.org/rsrf_funded_research/3.2.6.html#minassian

Mutations in MECP2 are a cause of Rett syndrome. Recently, a new isoform of MeCP2 was described, which has an alternative N-terminus, transcribed from exon 1. We screened exon 1 and the promoter region of MECP2 in 97 mutation-negative Rett syndrome cases. We found two sequence variants, but there was no evidence that they are pathogenic. Mutations in exon 1 and the promoter of MECP2 are not a common cause of Rett syndrome.European Journal of Human Genetics advance online publication, 15 September 2004; doi:10.1038/sj.ejhg.5201270

The new form of MeCP2 is 3% longer. Since about 15% of patients with a clinical diagnosis of Rett Syndrome are testing negative for mutation screening it is feasible that some have mutations in this "longer" area of the new form of the protein. This paper describes the analysis of 97 blood samples and states that no mutations were found.

Although rare, mutations in this area (called exon 1) have been identified. If your daughter has tested negative and you wish to have her tested for mutations in exon 1 please visit www.bcmgeneticlabs.org/tests/alltests.html.

Rett syndrome is a neurodevelopmental disorder that almost exclusively affects females. In addition to neurodevelopmental regression and loss of hand skills, apraxia, deceleration of head growth, and increasing spasticity and scoliosis, a number of behavioural features are also seen, including stereotypic hand movements, hyperventilation and breath holding. The aim of the study was to investigate the extent to which analogue environmental conditions affected the frequency of repetitive hand behaviour in eight girls and young women with Rett syndrome. Method The frequency of repetitive hand movements was observed every 10 s for four 4-min sessions under the following conditions: Continuous Adult Attention, Adult Demands, Stimulation and No Stimulation. Results The frequency of repetitive hand movements was high - they occurred in above 60% of all intervals in all conditions for all participants and at nearly 100% for some participants in some conditions. For one participant the frequency of repetitive hand movements was somewhat reduced in the Stimulation condition; for another it was relatively increased in the No Stimulation condition. Conclusions Overall, environmental manipulations had relatively limited effects on repetitive hand behaviours. Repetitive hand behaviour in Rett syndrome may be maintained by automatic reinforcement or neurochemical processes and may not be primarily influenced by contingent reinforcement.

PMID: 15357687 [PubMed - in process]

Repetitive hand movements are a key symptom of Rett Syndrome. The investigators were interested in determining whether environmental conditions and stimuli had an effect on the intensity of hand behaviors. After careful assessment they determined that in fact the environment had little if no effect on repetitive hand behaviors.