MeCP2 Dysfunction in Rett Syndrome (2006) PDF

MeCP2 dysfunction in Rett syndrome and related disorders Paolo Moretti and Huda Y Zoghbi Rett syndrome, a neurodevelopmental disorder caused by and is the only pervasive developmental disorder with mutations in the X-linked gene encoding methyl-CpG-binding a known genetic ca...

MeCP2 dysfunction in Rett syndrome and related disorders Paolo Moretti and Huda Y Zoghbi Rett syndrome, a neurodevelopmental disorder caused by and is the only pervasive developmental disorder with mutations in the X-linked gene encoding methyl-CpG-binding a known genetic cause. Rett syndrome is caused by protein 2 (MeCP2), is a leading cause of mental retardation with mutations in the X-linked gene encoding methyl-CpG- autistic features in females. MECP2 mutations have also been binding protein 2 (MeCP2). It is estimated that one identified in individuals with a variety of clinical syndromes, out of every 10 000–15 000 females develops Rett syn- including mild learning-disability in females, neonatal drome ; however, MECP2 mutations cause a variety of encephalopathy in males, and psychiatric disorders, autism additional neurodevelopmental disorders in both females and X-linked mental retardation in both males and females. and males, and the overall prevalence of MECP2 muta- Furthermore, MECP2 duplications have been shown to cause a tions in the population remains unknown. This review progressive postnatal neurological disorder. MeCP2 is a highlights recent research developments in the study of transcriptional repressor that binds to methylated CpG Rett syndrome and related disorders. dinucleotides flanked by AT-rich segments and recruits a co- repressor complex, thereby altering chromatin structure. Neurological manifestations of classic Rett Subtle gene expression changes have been identified in Rett syndrome patients and mouse models; however, MeCP2 dysfunction has Girls with Rett syndrome are born after an uneventful also been shown to cause abnormalities of RNA splicing, pregnancy and delivery. They are normal at birth and suggesting a complex molecular pathogenesis. Discovering achieve expected developmental milestones until 6 to 18 which genes are misregulated in the absence of functional months of age, when they develop deceleration of head MeCP2 and demonstrating their role in causing neuronal growth, leading to microcephaly. They enter a period of dysfunction and disease manifestations are challenging but regression characterized by loss of acquired language, important steps for understanding the pathogenesis of Rett cognitive, social and motor skills. Cognitive impair- syndrome and related disorders. ments are a common feature of humans with MECP2 mutations. Language dysfunction and social withdrawal Addresses are also prevalent. Motor abnormalities include gait Baylor College of Medicine, One Baylor Plaza, T807, Mail Stop 225, apraxia, ataxia, spasticity, tremors and dystonia. Although Houston, TX 77030, USA early hand-skills are generally achieved, hand use is lost Corresponding author: Zoghbi, Huda Y (hzoghbi@bcm.tmc.edu) and is replaced by stereotypies consisting of midline hand-wringing, clapping and mouthing. Seizures and breathing abnormalities such as hyperventilation and Current Opinion in Genetics & Development 2006, 16:276–281 apnea are common [5,6]. This review comes from a themed issue on Genetics of disease MECP2 mutations in Rett syndrome and Edited by Andrea Ballabio, David Nelson and Steve Rozen related disorders MECP2 mutations account for up to 96% of classic Rett Available online 2nd May 2006 syndrome cases. The initial genetic studies showed that 0959-437X/$ – see front matter 70–75% of Rett syndrome cases had mutations in MECP2 # 2006 Elsevier Ltd. All rights reserved.. The spectrum of MECP2 mutations causing Rett DOI 10.1016/j.gde.2006.04.009 syndrome includes missense, frameshift and nonsense mutations, and intragenic deletions. Nearly 70% of the mutations arise from C–T transitions at eight CpG dinu- cleotides, whereas carboxy-terminal deletions are esti- Introduction mated to occur in 10–15% of patients. The MECP2 Rett syndrome (Online Mendelian Inheritance in Man gene, located in Xq28 and subject to X-chromosome [OMIM] database, 312750) is a postnatal neurodevelop- inactivation, comprises 4 exons spanning a region of more mental disorder characterized by loss of acquired motor than 75 kb in length. In 2004, MECP2 was shown to and language skills, autistic features, and unusual stereo- generate two separate isoforms: one in which the coding typed movements (see Glossary). First described as a region encompasses exons 1, 3 and 4; and a second in clinical entity by the pediatrician Andreas Rett in 1966 which the exon 1 sequence constitutes the 50 untranslated , Rett syndrome is classified in the Diagnostic and region, and the coding region spans exons 2, 3 and 4 Statistical Manual of Mental Disorders as a pervasive [8

,9

]. Exon 1-specific mutations are found in less than developmental disorder — a group of disorders also 1% of Rett syndrome cases, and mutations in exon 2 are including classic autism and Asperger’s syndrome — even less common. Interestingly, mutations predicted to Current Opinion in Genetics & Development 2006, 16:276–281 www.sciencedirect.com  MeCP2 dysfunction in Rett syndrome and related disorders Moretti and Zoghbi 277 Glossary are boys with mutations that are not found in girls with Cre-lox technology: A technology that enables selective deletion of Rett syndrome, presumably because their effects are mild sequences in vivo. The Cre recombinase recognizes specific DNA sequences known as LoxP sites and mediates recombination in heterozygosity. Finally, a minority of individuals with a between them, which, in turn, will result in the excision of sequences Rett-like phenotype associated with early-onset seizures flanked by the two LoxP sites. were found to have mutations in CDKL5 (CYCLIN- Reporter minigene: An artificial DNA construct containing only a DEPENDENT KINASE-LIKE 5), a gene also known to selected portion of a gene and designed to test aspects of gene regulation in cells in vitro. cause early-onset epilepsy and severe mental retardation Stereotyped movements: Repetitive, non-purposeful and. Recent data also indicate that increased MECP2 nonfunctional motor behaviors (e.g. hand-wringing, waving or gene-dosage can disrupt normal brain function. Interest- mouthing). ingly, the first demonstration that slightly increased levels of MeCP2 protein were deleterious came from experi- ments in transgenic mice that demonstrated progressive affect the function of either isoform alone cause Rett neurological dysfunction in animals that overexpress syndrome (B Roa, personal communication) [9

]. At MECP2 under control of its native promoter at twice Baylor College of Medicine, sequence changes in MECP2 the normal levels [11

]. Duplications spanning the were identified in 96% of 125 classic Rett syndrome MECP2 locus were identified in a girl with features of patients, and large deletions and insertions were found Rett syndrome in the presence of preserved speech [12
], in 10% of these patients. It remains to be determined a boy with severe mental retardation and clinical features whether the 4% of Rett syndrome cases with no detect- of Rett syndrome [13
], several patients with severe able sequence alterations carry mutations elsewhere in mental retardation and progressive spasticity [14
], and the gene, including in its regulatory regions. members of three families with non-specific X-linked mental retardation [15
]. Mutations in MECP2 have also been identified in female patients with phenotypes distinct from the classic pre- Methyl-CpG-binding protein 2 sentation of Rett syndrome (Table 1). Mutation type and Current data support a model in which MeCP2 functions X-chromosome inactivation patterns are two known as a DNA methylation-dependent transcriptional repres- sources of phenotypic variability. Males with MECP2 sor. MeCP2 was initially identified in a southwestern mutations fall into three main categories: boys with Rett assay as an 80 kDa protein able to bind to DNA oligo- syndrome; boys with severe encephalopathy and infantile nucleotides containing at least one symmetrically methy- death; and boys with less severe neurological and/or lated CpG dinucleotide. The protein was shown to psychiatric manifestations (Table 1). Boys in the first contain a methyl-CpG-binding domain required for bind- category have a 47,XXY karyotype or are somatic mosaic ing to methylated DNA in vitro and for localization to and carry the same MECP2 mutations that cause classic highly methylated pericentromeric heterochromatin in Rett syndrome in girls. Boys in the second group carry cells in culture [17,18]. Recent data demonstrated that MECP2 mutations identical to those found in Rett syn- high-affinity binding of MeCP2 to DNA requires the drome; these mutations are generally thought to disrupt presence of AT-rich sequences adjacent to the CpG site DNA binding or nuclear localization. In the third group [19

]. The first indication of the physiological role of Table 1 Clinical phenotypes of MeCP2 dysfunction Loss-of-function MECP2 alleles Females Males Classic Rett syndrome Infantile encephalopathy Atypical Rett (preserved speech or normal hand use) Rett syndrome if mosaic or XXY Infantile encephalopathy Mental retardation with motor deficits Angelman syndrome phenotype Early-onset bipolar disorder Mental retardation with seizures Early-onset schizophrenia Mild mental retardation Learning disability Autism Normal MECP2 gene duplications Preserved speech variant of Rett syndrome Severe mental retardation and clinical features of Rett syndrome Severe mental retardation and progressive spasticity Non-specific X-linked mental retardation The information used to form this table comes from various studies [5,6,12
–15
,16]. www.sciencedirect.com Current Opinion in Genetics & Development 2006, 16:276–281 278 Genetics of disease MeCP2 came from experiments showing that the protein the forebrain, hippocampus and brainstem caused repressed transcription in vitro and in cells. The delayed onset of phenotypes similar to those shown by transcriptional repression domain of MeCP2 was able Mecp2 knockout mice , indicating that Mecp2 plays an to repress transcription from up to 2 kb from the mRNA essential role in post-mitotic neurons. Shahbazian et al. initiation site and is associated with the Sin3A– inserted a stop codon into Mecp2 at the nucleotide HDAC1–HDAC2 co-repressor complex [21,22]. Several position corresponding to amino acid 309, thereby gen- additional MeCP2-interacting proteins were subse- erating a mouse with a truncating mutation of Mecp2 quently identified, including the transcription factor (Mecp2308). This mutation caused a milder phenotype TFIIB, the proto-oncogenic protein c-ski, the DNA than that shown by the previous two mouse models, methyltransferase DNMT1, the histone methyltransfer- and in male mice it recapitulated many of the neurological ase Suv39H1, and Brahma, a component of the SWI–SNF phenotypes seen in girls with Rett syndrome. For chromatin remodeling complex [23–26]. However, in the instance, the mice appear normal until about six weeks absence of functionally relevant genetic targets of of age, after which they develop forepaw stereotypies, MeCP2, the biological relevance of these interactions slowly progressive motor dysfunction , social behavior remains unclear. For instance, analysis of nuclear extracts impairments , and learning and memory deficits [34
]. from rodent tissues, cultured cells and Xenopus laevis oocytes revealed that only a small fraction of MeCP2 To investigate the cell biological mechanisms and devel- interacts with Sin3a, and that the interaction is not stable opmental stages regulated by Mecp2 in neurons, Matar- [27
]. MeCP2 purified from rat brain did not stably azzo et al. studied the maturation of the olfactory associate with any proteins and behaved consistently as system. They showed that Mecp2 knockout mice demon- a monomeric protein with an elongated shape [27
]. strate a transient delay in the differentiation of olfactory These findings demonstrate that MeCP2 is not an obli- neurons, and abnormalities of axonal targeting in the gate or stable component of the Sin3a co-repressor com- olfactory bulb, suggesting that Mecp2 mediates a crucial plex and suggest that MeCP2 might interact with a function in the final stages of neuronal development. diverse range of cofactors. Recent data showed that neuronal electrophysiological abnormalities are present in all three mouse models of Recent results suggest that the function of MeCP2 might Rett syndrome [34
,36
,37
], demonstrating that neuronal be more complex than previously anticipated. For dysfunction is part of the pathogenesis of the disease. In instance, purified recombinant MeCP2 was shown to have addition, Mecp2308 mice were shown to have deficits of a high-affinity RNA binding activity that is mutually memory and spatial learning [34
], suggesting that the exclusive to its methyl-CpG-binding properties and does cognitive disturbances that are characteristic of Rett not require the methyl-CpG-binding domain. Inter- syndrome can be modeled in these mice. Interestingly, estingly, although the biological significance of a MeCP2– Mecp2 knockout mice showed smaller, less complex pyr- RNA complex remains to be elucidated, recent data amidal neurons in cortical layers II and III, with asso- indicated that MeCP2 interacts with the RNA-binding ciated thinning of neocortical projection layers. By protein Y box-binding protein 1 (YB1) and regulates contrast, the morphology of neurons and dendrites was splicing of reporter minigenes (see Glossary) [29

]. unaltered in the neocortex and hippocampus of sympto- Importantly, aberrant RNA-splicing patterns were iden- matic and asymptomatic Mecp2308 mice [34
]. These mice tified in Mecp2 mutant mice [29

]. The finding that demonstrated only subtle alterations in the length of the MeCP2 regulates transcription and splicing of some of postsynaptic density at excitatory synapses. Breathing its targets suggests the existence of multiple layers of disturbances occur in a significant fraction of Rett syn- epigenetic regulation. drome patients, and sudden respiratory arrhythmia is thought to be the cause of death in some cases. Mouse models of Rett syndrome Norepinephrine plays an important role in the physiology Three mouse models of Rett syndrome have been gen- of the respiratory system, and its metabolite, 3-methoxy- erated, each with different mutation type and phenotype 4-hydroxyphenylethylene glycol, was shown to be severity. Using Cre-lox technology (see Glossary), Chen reduced in the cerebrospinal fluid of Rett syndrome et al. and Guy et al. generated mice with fully patients [40,41]. Recent work with Mecp2 knockout mice deleted Mecp2 sequences (i.e. Mecp2 knockout mice). linked these clinical observations to disruption of nore- Mutant mice showed a period of apparently normal pinephrine and respiratory systems. development followed by severe progressive neurological dysfunction leading to death at 7–10 weeks. Mutation of Expression of Mecp2 in post-mitotic neurons of Mecp2-null Mecp2 restricted to neuronal lineages resulted in a phe- mice was shown to be sufficient to restore normal neu- notype indistinguishable from that of mice lacking Mecp2 rological function, indicating that Mecp2 deficiency in in all tissues, demonstrating that absence of normal peripheral tissues does not significantly influence disease protein function in neurons is sufficient to cause disease manifestations and suggesting that Mecp2 plays no essen- [30,31]. Inactivation of Mecp2 in post-mitotic neurons of tial role in the early stages of brain development [43
]. Current Opinion in Genetics & Development 2006, 16:276–281 www.sciencedirect.com  MeCP2 dysfunction in Rett syndrome and related disorders Moretti and Zoghbi 279 However, twofold overexpression of Mecp2 in wild type neurons. Thus, a key challenge for the future will be mice resulted in the development of progressive neuro- the identification of genes regulated by MeCP2 in the logical deterioration with seizures, motor dysfunction and brain, and the elucidation of the mechanisms by which reduced survival [11

]. This finding indicates that Mecp2 MECP2 mutations give rise to the characteristic features levels must be tightly regulated in vivo and has important of Rett syndrome. The full extent of disease manifesta- implications for gene therapy. tions caused by MECP2 mutations and gene dosage effects also remains to be explored. Knowledge that levels Target genes of MeCP2 of MeCP2 are crucial to normal cell function and that the Although biochemical evidence suggested that MeCP2 protein plays a role in synaptic function and neuronal functions as a global repressor of gene expression, tran- plasticity suggests that specific hypomorphic mutations or scriptional profiling failed to identify profound changes of variants might also contribute to late onset neurological gene expression in the brain of Mecp2 knockout mice. syndromes. Surprisingly, in these mice, minor changes in gene expression were found that became significant only when Acknowledgements groups of genes were analyzed together. Subsequent The authors wish to thank members of the Zoghbi laboratory for feedback. We are grateful to Jeff Neul, Aaron Bowman and Bryan McGill studies using a variety of approaches identified several for their critical reading of the manuscript. PM is supported by National putative target genes of MeCP2 in rodents and/or humans Institutes of Health (NIH) NS049181, and March of Dimes Basil [45–47,48

,49]. For example, a candidate approach iden- O’Connor Starter Scholar Research Award; HYZ is supported by NIH HD40301, funds from Cure Autism Now, and NIH HD24064 to the tified overexpression of brain-derived neurotrophic factor Baylor College of Medicine Mental Retardation and Developmental (BDNF) in Mecp2 knockout neurons in culture [45,46]. Disabilities Research Center. HYZ is an investigator with the Howard Hughes Medical Institute. Interestingly, recent data showed that BDNF protein levels are decreased, not increased, in the brain of Mecp2 knockout mice. These apparently contradictory results References and recommended reading Papers of particular interest, published within the annual period of can be explained by the observation that Mecp2 knockout review, have been highlighted as: mice show reduced neuronal activity — of unknown
of special interest cause — and this might decrease BDNF expression.

of outstanding interest Thus, in vivo neuronal dysfunction might counteract the direct effect of loss of Mecp2 function on BDNF 1. Hagberg B, Aicardi J, Dias K, Ramos O: A progressive syndrome transcription, with the net effect of reducing BDNF brain of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett’s syndrome: report of 35 cases. Ann Neurol 1983, levels. Mecp2 deficiency was also shown to cause 14:471-479. reduced expression of Ube3a (ubiquitin protein ligase E3A) 2. Rett A: [On a unusual brain atrophy syndrome in and Gabrb3 (b3 GABA receptor) in mouse brain ; hyperammonemia in childhood]. Wien Med Wochenschr 1966, however, the mechanism of this effect remains unclear. 116:723-726. Dlx5 and glucocorticoid-regulated genes were shown to 3. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, be misexpressed in the brain of mutant mice, and this Zoghbi HY: Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet effect was thought to be directly based on the binding of 1999, 23:185-188. Mecp2 to the regulatory regions of these genes. Overall, 4. Percy AK: Rett syndrome. Current status and new vistas. the magnitude of these transcriptional effects is small; Neurol Clin 2002, 20:1125-1141. however, it remains possible that subtle changes of gene 5. Neul JL, Zoghbi HY: Rett syndrome: a prototypical expression contribute to some aspects of the Rett syn- neurodevelopmental disorder. Neuroscientist 2004, 10:118-128. drome phenotype. To date, there is no evidence linking a 6. Zoghbi HY: MeCP2 dysfunction in humans and mice. specific transcriptional change caused by loss of Mecp2 J Child Neurol 2005, 20:736-740. function to a phenotypic abnormality characteristic of the 7. Shahbazian MD, Zoghbi HY: Molecular genetics of Rett disease. syndrome and clinical spectrum of MECP2 mutations. Curr Opin Neurol 2001, 14:171-176. 8. Kriaucionis S, Bird A: The major form of MeCP2 has a novel Conclusions

N-terminus generated by alternative splicing. Nucleic Acids The identification of the genetic cause of Rett syndrome, Res 2004, 32:1818-1823. a predominantly sporadic disease, was a major advance in The authors describe the identification of a novel, alternatively spliced isoform of MeCP2. This isoform represents >90% of total MeCP2 in the clinical neurology and genetics. In addition to enabling brain. precise molecular diagnosis and genetic counseling, this 9. Mnatzakanian GN, Lohi H, Munteanu I, Alfred SE, Yamada T, discovery underscored the value of focusing on a handful

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MeCP2 in postmitotic neurons rescues Rett syndrome in mice. structure at the Dlx5–Dlx6 locus in Mecp2 knockout mice and demon- Proc Natl Acad Sci USA 2004, 101:6033-6038. strate that formation of a silent-chromatin loop is a mechanism underlying The authors show that expression of MeCP2 in post-mitotic neurons gene regulation by MeCP2. rescues the phenotypic abnormalities of Mecp2 knockout mice. 44. Tudor M, Akbarian S, Chen RZ, Jaenisch R: Transcriptional 49. Nuber UA, Kriaucionis S, Roloff TC, Guy J, Selfridge J, profiling of a mouse model for Rett syndrome reveals subtle Steinhoff C, Schulz R, Lipkowitz B, Ropers HH, Holmes MC et al.: transcriptional changes in the brain. Proc Natl Acad Sci USA Up-regulation of glucocorticoid-regulated genes in a 2002, 99:15536-15541. mouse model of Rett syndrome. Hum Mol Genet 2005, 14:2247-2256. 45. Chen WG, Chang Q, Lin Y, Meissner A, West AE, Griffith EC, Jaenisch R, Greenberg ME: Derepression of BDNF transcription 50. Chang Q, Khare G, Dani V, Nelson S, Jaenisch R: The disease involves calcium-dependent phosphorylation of MeCP2. progression of Mecp2 mutant mice is affected by the level of Science 2003, 302:885-889. BDNF expression. Neuron 2006, 49:341-348. Elsevier celebrates two anniversaries with gift to university libraries in the developing world In 1580, the Elzevir family began their printing and bookselling business in the Netherlands, publishing works by scholars such as John Locke, Galileo Galilei and Hugo Grotius. On 4 March 1880, Jacobus George Robbers founded the modern Elsevier company intending, just like the original Elzevir family, to reproduce fine editions of literary classics for the edification of others who shared his passion, other ’Elzevirians’. Robbers co-opted the Elzevir family printer’s mark, stamping the new Elsevier products with a classic symbol of the symbiotic relationship between publisher and scholar. Elsevier has since become a leader in the dissemination of scientific, technical and medical (STM) information, building a reputation for excellence in publishing, new product innovation and commitment to its STM communities. In celebration of the House of Elzevir’s 425th anniversary and the 125th anniversary of the modern Elsevier company, Elsevier donated books to ten university libraries in the developing world. Entitled ’A Book in Your Name’, each of the 6700 Elsevier employees worldwide was invited to select one of the chosen libraries to receive a book donated by Elsevier. The core gift collection contains the company’s most important and widely used STM publications, including Gray’s Anatomy, Dorland’s Illustrated Medical Dictionary, Essential Medical Physiology, Cecil Essentials of Medicine, Mosby’s Medical, Nursing and Allied Health Dictionary, The Vaccine Book, Fundamentals of Neuroscience, and Myles Textbook for Midwives. The ten beneficiary libraries are located in Africa, South America and Asia. They include the Library of the Sciences of the University of Sierra Leone; the library of the Muhimbili University College of Health Sciences of the University of Dar es Salaam, Tanzania; the library of the College of Medicine of the University of Malawi; and the University of Zambia; Universite du Mali; Universidade Eduardo Mondlane, Mozambique; Makerere University, Uganda; Universidad San Francisco de Quito, Ecuador; Universidad Francisco Marroquin, Guatemala; and the National Centre for Scientific and Technological Information (NACESTI), Vietnam. Through ‘A Book in Your Name’, these libraries received books with a total retail value of approximately one million US dollars. For more information, visit www.elsevier.com www.sciencedirect.com Current Opinion in Genetics & Development 2006, 16:276–281