Rett syndrome (RTT) is an inherited neurodevelopmental disorder of females that occurs once in 10,000-15,000 births. Affected females develop normally for 6-18 months, but then lose voluntary movements, including speech and hand skills. Most RTT patients are heterozygous for mutations in the X-linked gene MECP2 (refs. 3-12), encoding a protein that binds to methylated sites in genomic DNA and facilitates gene silencing. Previous work with Mecp2-null embryonic stem cells indicated that MeCP2 is essential for mouse embryogenesis. Here we generate mice lacking Mecp2 using Cre-loxP technology. Both Mecp2-null mice and mice in which Mecp2 was deleted in brain showed severe neurological symptoms at approximately six weeks of age. Compensation for absence of MeCP2 in other tissues by MeCP1 (refs. 19,20) was not apparent in genetic or biochemical tests. After several months, heterozygous female mice also showed behavioral symptoms. The overlapping delay before symptom onset in humans and mice, despite their profoundly different rates of development, raises the possibility that stability of brain function, not brain development per se, is compromised by the absence of MeCP2.

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A mouse Mecp2-null mutation causes neurological symptoms that mimic rett syndrome

Post-transcriptional gene regulation (PTGR) concerns processes involved in the maturation, transport, stability and translation of coding and non-coding RNAs. RNA-binding proteins (RBPs) and ribonucleoproteins coordinate RNA processing and PTGR. The introduction of large-scale quantitative methods, such as next-generation sequencing and modern protein mass spectrometry, has renewed interest in the investigation of PTGR and the protein factors involved at a systems-biology level. Here, we present a census of 1,542 manually curated RBPs that we have analysed for their interactions with different classes of RNA, their evolutionary conservation, their abundance and their tissue-specific expression. Our analysis is a critical step towards the comprehensive characterization of proteins involved in human RNA metabolism.

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A census of human RNA-binding proteins.

Mecp2 is an X-linked gene encoding a nuclear protein that binds specifically to methylated DNA (ref. 1) and functions as a general transcriptional repressor by associating with chromatin-remodeling complexes. Mecp2 is expressed at high levels in the postnatal brain, indicating that methylation-dependent regulation of gene expression may have a crucial role in the mammalian central nervous system. Consistent with this notion is the recent demonstration that MECP2 mutations cause Rett syndrome (RTT, MIM 312750), a childhood neurological disorder that represents one of the most common causes of mental retardation in females. Here we show that Mecp2-deficient mice exhibit phenotypes that resemble some of the symptoms of RTT patients. Mecp2-null mice were normal until 5 weeks of age, when they began to develop disease, leading to death between 6 and 12 weeks. Mutant brains showed substantial reduction in both weight and neuronal cell size, but no obvious structural defects or signs of neurodegeneration. Brain-specific deletion of Mecp2 at embryonic day (E) 12 resulted in a phenotype identical to that of the null mutation, indicating that the phenotype is caused by Mecp2 deficiency in the CNS rather than in peripheral tissues. Deletion of Mecp2 in postnatal CNS neurons led to a similar neuronal phenotype, although at a later age. Our results indicate that the role of Mecp2 is not restricted to the immature brain, but becomes critical in mature neurons. Mecp2 deficiency in these neurons is sufficient to cause neuronal dysfunction with symptomatic manifestation similar to Rett syndrome.

Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice

https://www.cell.com/neuron/pdf/S0896-6273(07)00756-8.pdf

The Story of Rett Syndrome: From Clinic to Neurobiology

DNA methylation has recently moved to centre stage in the aetiology of human neurodevelopmental syndromes such as the fragile X, ICF and Rett syndromes. These diseases result from the misregulation of genes that occurs with the loss of appropriate epigenetic controls during neuronal development. Recent advances have connected DNA methylation to chromatin-remodelling enzymes, and understanding this link will be central to the design of new therapeutic tools.

DNA methylation in health and disease

Rett syndrome (RTT) is a neurodevelopmental disorder characterized by loss of acquired skills after a period of normal development in infant girls. The responsible gene, encoding methyl-CpG binding protein 2 (MeCP2), was recently discovered. Here we explore the spectrum of phenotypes resulting from MECP2 mutations. Both nonsense (R168X and R255X) and missense (R106W and R306C) mutations have been found, with multiple recurrences. R168X mutations were identified in six unrelated sporadic cases, as well as in two affected sisters and their normal mother. The missense mutations were de novo and affect conserved domains of MeCP2. All of the nucleotide substitutions involve C→T transitions at CpG hotspots. A single nucleotide deletion, at codon 137, that creates a L138X stop codon within the methyl-binding domain was found in an individual with features of RTT and incontinentia pigmenti. An 806delG deletion causing a V288X stop in the transcription-repression domain was identified in a woman with motor-coordination problems, mild learning disability, and skewed X inactivation; in her sister and daughter, who were affected with classic RTT; and in her hemizygous son, who died from congenital encephalopathy. Thus, some males with RTT-causing MECP2 mutations may survive to birth, and female heterozygotes with favorably skewed X-inactivation patterns may have little or no involvement. Therefore, MECP2 mutations are not limited to RTT and may be implicated in a much broader phenotypic spectrum.

Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots.

The identification of mutations in the gene encoding methyl CpG binding protein 2 (MeCP2) in Rett syndrome represents a major advance in the field. The current model predicts that MeCP2 represses transcription by binding methylated CpG residues and mediating chromatin remodeling. A physical interaction between MeCP2, histone deacetylases and the transcriptional co-repressor Sin3A has been demonstrated, as well as an association of MeCP2 with the basal transcription apparatus. It is unclear, however, whether MeCP2-mediated chromatin remodeling is necessary for transcriptional repression in vivo. Eight recurrent missense and nonsense mutations account for >65% of the mutations identified in Rett syndrome probands, and as predicted from the sporadic nature of the disorder, most mutations are de novo. The severity of the phenotype is likely to reflect the pattern of X chromosome inactivation in relevant tissues, although the type and position of the mutation may also play a role. Although much is known about the biochemical function of MeCP2, the phenotype of Rett syndrome suggests that it plays an unexplored but critical role in development and maintenance of the nervous system.

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Rett syndrome: a surprising result of mutation in MECP2

The neurologic disorder Rett syndrome was originally described exclusively in girls. We present two boys with clinical features of Rett syndrome. Other than head circumference deceleration, no longer considered mandatory, patient 1 meets all of the criteria. Using fluorescent in situ hybridization analysis, 97.6% of cells were found to be karyotypically normal (46,XY). No mutation was detected on screening of the coding region of the MECP2 gene. The second patient also has classic features of Rett syndrome. However, cytogenetic analysis of peripheral blood revealed a karyotype 47,XXY[23]/46,XY[7] confirming mosaicism for Klinefelter's syndrome. A T158M missense mutation in the methylcytosine-binding domain of the MECP2 gene was identified. A diagnostic bias against the clinical identification of Rett syndrome in boys may exist. This presentation of the male phenotype could be more common than it would appear, although boys with MECP2 mutations might also manifest in other ways. Rett syndrome remains a clinical diagnosis that should not be dismissed in boys, and thorough evaluation including karyotype and mutation testing is warranted.

Isa Houwink-Manville

Papers

Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots.

Rett syndrome: a surprising result of mutation in MECP2

Occurrence of Rett Syndrome in Boys