MECP2-Related Disorders in Males: Comparison
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Please note this is a comparison between Version 2 by Amina Yu and Version 1 by Judith Armstrong.

Methyl CP2pG binding protein 2 ( MECP2 ) is an unstructured protein that can adopt local secondary structures when binding to other molecules, which explains its involvement in multiple molecular interactions and thereby, functions. Thus,MECP2 MECP2 is a multifunctional gene that acts as a transcriptional regulator (both activating and repressing) and a chromatin remodeler; it also interacts with the RNA splicing machinery and with microRNA processing machinery, among others. Post-translational modifications are also implicated in regulating its activity and interactions with other proteins.

  • Rett syndrome
  • duplication syndrome
  • encephalopathy
  • point mutation
  • loss-of-function
  • males

1. MECP2 Gene

Methyl CpG binding protein 2 ( MECP2 ) (OMIM *300005) encodes the protein MeCP2 and is located in the Xq28 region which can be inactivated for gene dosage compensation of the X chromosome in females [1]. MECP2 has four exons and undergoes alternative splicing from which two well-characterized isoforms are generated—isoform e1 and isoform e2. Isoform e1 retains exons 1, 3, and 4 whereas isoform e2 retains exons 2, 3, and 4. MECP2_e1 is conserved across vertebrates while e2 appeared later in the class Mammalia [2]. MECP2_e1 is the most abundant isoform in the brain although the ratio between the two isoforms varies across different tissues; for example, MECP2_e2 is more abundant in fibroblasts [2]. Even though both isoforms share the majority of their sequence and the main functional domains, they are not completely redundant. Each of them has their own properties, spatial expression, function, and interacting partners [3,4,5][3][4][5].

MECP2 has several structural domains—N-terminal domain (NTD), methyl-binding domain (MBD), intervening domain (ID), transcriptional repression domain (TRD), and C-terminal domain (CTD). MBD and TRD are considered crucial functional domains. MBD enables the binding to methyl CpG dinucleotides and is where most of disease-causing mutations are located. TRD is needed for the binding and posterior recruitment of co-repressor proteins, such as NCoR, SMRT, and HDAC3, in order to repress transcription [6]. The protein has a nuclear localization signal (NLS) domain as well. MeCP2 is an unstructured protein that can adopt local secondary structures when binding to other molecules, which explains its involvement in multiple molecular interactions and thereby, functions [7,8][7][8]. Thus, MECP2 is a multifunctional gene that acts as a transcriptional regulator (both activating and repressing) and a chromatin remodeler; it also interacts with the RNA splicing machinery and with microRNA processing machinery, among others [9]. Post-translational modifications are also implicated in regulating its activity and interactions with other proteins [10,11][10][11]. The resultant protein MeCP2 is ubiquitously expressed even though it is more abundant in the brain, especially in neuronal cells. It is noteworthy that the level of expression correlates with the maturation of neurons, indicating the importance of MeCP2 not only in neuronal development but also in neuronal maturation and maintenance [12,13][12][13].

Since mutations in the MECP2 gene were first reported in 1999 in female and male patients with Rett syndrome (RTT) (OMIM #312750) [14,15][14][15] , genetic alterations ranging from single nucleotide mutations to large deletions have been described and associated with RTT. As the majority of the reported cases described affected females, it was suggested that mutations in MECP2 lead to embryonic lethality or early postnatal death in males, since no wildtype allele can be partially expressed as in females. However, sporadic reports of boys with mutations in this gene have shown otherwise [15,16,17,18,19][15][16][17][18][19].

As can be inferred, MECP2 is a dosage-sensitive gene because loss-of-function mutations lead to RTT, but whole gene duplication leads to MECP2 duplication syndrome(MDS). This must be taken into consideration when looking for a treatment. Here, we would like to take a deeper look into the male cases harboring mutations and alterations in MECP2 since much remains to be understood.

2. Mutations in MECP2

Whenever a mutation in MECP2 is found in a patient, RTT becomes a possible diagnosis. RTT was first clinically described in 1966 by Andreas Rett in girls. In 1999, Zoghbi’s group linked MECP2 to RTT [14,15][14][15]. Since then, groups all over the world have reported patients, reaching a few thousands of cases. In fact, MECP2 mutations cause 97% of classic RTT cases [20,21][20][21].

Several specific MECP2 mutation screenings have been performed in males affected by neurological disorders. In all of them, a low frequency of variants in MECP2 was found [22,23,24,25][22][23][24][25]. RettBASE is an international curated database, which gathers the genetic variation found in individuals with RTT and related clinical disorders. To date, there have been 3924 female cases with mutations in MECP2 and 345 male cases. As in females, in males, mutations range from single nucleotide changes to larger deletions involving up to 240 nt [26,27][26][27]. Small duplications from one to seven nucleotides have also been reported in RettBASE. The disparity of cases for each sex and the difficulties in creating the first male mouse model suggested that mutations in MECP2 in males were lethal. Fortunately, different groups have reported new patients and, nowadays, it we knowas known that the effects of these mutations range from severe neonatal encephalopathies and premature death (as in the case of c.806delG [26]) to mild intellectual and psychomotor impairment (as in c.608C > T [19]) and that they are not always related to RTT.

In 2003, Ravn et al. compared the first group of 18 male patients with pathogenic variants in MECP2 . They classified the variants into two groups—mutations causing RTT in girls and mutations that do not affect or cause mild intellectual disability (ID) in females. This genetic classification corresponds with the phenotypes of the boys, which are divided into two groups as well—cases with severe neonatal encephalopathy and cases with non-specific mental retardation. They pointed out that, among the patients harboring RTT mutations, two kinds of patients could be found. Whenever the patient has Klinefelter syndrome (47, XXY) or is a mosaic, the boy develops an RTT phenotype. However, if the chromosomal complement is normal and no mosaicisms are found, the boy usually dies at a very early age [26].

The incorporation of next generation sequencing (NGS), especially of gene panels, has helped reduce the time needed for a molecular diagnosis in patients with rare diseases because of its ability to multiplex genes and patients. NGS has enabled the finding of the molecular cause in patients with either a more recognizable RTT phenotype and for whom traditional techniques were unable to detect a variation, or a more ambiguous phenotype such as X-linked intellectual disability [42,43,44][28][29][30]. The implementation of NGS as a diagnostic tool has found new patients with MECP2 variations, especially males, who otherwise might never have been redirected for a MECP2 direct sequencing test [own data]. In addition, NGS-based methods possess a high read coverage for the amplified genes which makes them a technique to take seriously into consideration for mosaicism detection rather than Sanger sequencing [45][31].

3. Duplication of MECP2

In the late 1990s, several groups were trying to link patients with X-linked mental retardation (XLMR) to specific genetic alterations or genes. During this search, several cases with X chromosome distal duplications were reported [47][32]. In particular, Lubs et al., described a family of five affected boys with an Xq28 duplication inherited from carrier mothers which later were confirmed to be proper cases of MDS [48,49][33][34]. Because of that first article, MDS was originally named as Lubs X-linked mental retardation syndrome, a name that still can be found in OMIM (MIM #300260). In 2005, publications of well-characterized new cases with duplications encompassing MECP2 led to the establishment of the MDS as we know it nowadays [47,50,51].

Even though MDS is a rare syndrome and most of the articles describe sporadic or small familiar cases rather than large cohorts, to date, there are more than 600 cases reported worldwide [47,48,49,50,51,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108][109][110][111][112][113].

As mentioned, some clinical features, such as epilepsy, respiratory tract infections, or constipation, appear or worsen with age. As a result, Peters et al., reported that their older participants have more severe clinical symptoms, specifically regarding motor dysfunction (e.g., dystonia, scoliosis, and/or rigidity) and functional skills (e.g., motor skills, communication skills, chewing, and swallowing) [129][111]. A longitudinal Japanese study found a similar outcome by comparing the clinical traits of MDS boys at their first medical visit and some years later [130][112].

The location of the duplications has been studied as well. It was thought that girls with translocations of the duplications to autosomal chromosomes were more severely affected than girls with interstitial duplications, since the former escape XCI [74,106][56][88]. However, females with duplications in tandem and a severe phenotype have also been reported [86][68]. In our personal experience with a Spanish cohort, a boy with a duplication in the Y chromosome was the most severely affected individual and died before one year of age. Nevertheless, we know another boy with an even larger duplication in the Y chromosome who is still alive [123].

4. Modeling RTT and MDS for Future Therapies

We would not like to end this review without briefly mentioning the advantages of in vitro and preclinical models. The difficulty in accessing target tissue samples from children affected by neurodevelop mental disorders has encourage researchers to create specific animal and cellular models to gain knowledge of rare diseases as RTT and MDS. In RTT, the most frequently used animal model has been the male Mecp2 -null mouse ( Mecp2 −/y ) which manifests the early severe phenotype seen in humans [137][114]. Despite being the major source of findings related to mechanisms and pathways in RTT, the translatability of mouse models towards humans is not clear, especially regarding RTT females. Several mouse models for MDS have also been created [138,139][115][116]. Alternative models, such as primary cultures of patients’ peripheral tissues, human embryonic stem cells (hESCs), or human-induced pluripotent stem cells (hiPSCs) reprogrammed from patients’ somatic cells, have proven to be very useful [103,140][85][117]. Tang and colleagues found that in hiPSCs of a male RTT patient, elevating KCC2 levels could ameliorate the functional deficits caused by the absence of MeCP2, and showed that IGF1 treatment works in the mentioned tissue [141,142][118][119]. Kim et al., also found that in RTT hiPSC knockdown of LIN28 expression partially reversed the synaptic deficits [143][120]. Recently, 3D aggregates from hiPSCs have been developed in an attempt to mimic the complex architecture and functions of organs such as the brain [144][121]. Moreover, region-specific brain organoids have been generated. The created organoids have also proven to be mutation-dependent and different initial phenotypic alterations have been found in organoids with different backgrounds [145][122]. All these in vitro human-derived models seem truly promising, not only because of the molecular and genetic insight they are generating, but also because several drugs are being tested and these could, ultimately, undergo clinical trials.

Even though most of the clinical trials for RTT have female participants, according to the register of the U.S. National Library of Medicine a few clinical trials have incorporated male patients. Such is the case of NCT00593957, NTC01520363 with dextromethorphan, NCT02790034 with sarizotan, and NCT00299312, in which a phase of genetic and physical characterization of RTT patients has been done. On the other hand, there are no clinical trials registered yet for MDS, but some promising results have been obtained in the previous in vitro and animal models. Recently, Ash etand so al.on, found that the hyperactivity seen in ERK the pathway in MDS could, similar to other autism-associated disorders, be reversed with ERK-specific pharmacologic inhibitors [146,147][123][124]. Moreover, antisense oligonucleotide (ASO) therapies are showing promising results in mice, especially because of their ability to reduce MeCP2 expression in a dose-dependent manner [139][116]. TheseIt results showwas showed that CNS administration of MECP2 -ASO is well tolerated and beneficial in a mouse model. Although these first studies do not include the IRAK1 gene, they provide a translatable approach that could be feasible for treating MDS. The CRISPR-Cas system has been tested in animal models and human primary fibroblasts and has successfully corrected the duplication of MECP2 MECP2 including IRAK1 [140][117]. However, there is not enough evidence so far to suggest possible approaches to therapy targeted the pathophysiology underlying these two diseases. Further work could bring deep brain stimulation, ASO, and gene therapy into the clinic within the coming decades [8].

References

  1. Xinhua, B.; Shengling, J.; Fuying, S.; Hong, P.; Meirong, L.; Wu, X.R. X chromosome inactivation in rett syndrome and Its correlations with mecp2 mutations and phenotype. J. Child Neurol. 2008, 23, 22–25.
  2. Mnatzakanian, G.N.; Lohi, H.; Munteanu, I.; Alfred, S.E.; Yamada, T.; MacLeod, P.J.M.; Jones, J.R.; Scherer, S.W.; Schanen, N.C.; Friez, M.J.; et al. A previously unidentified MECP2 open reading frame defines a new protein isoform relevant to Rett syndrome. Nat. Genet. 2004, 36, 339–341.
  3. Dastidar, S.G.; Bardai, F.H.; Ma, C.; Price, V.; Rawat, V.; Verma, P.; Narayanan, V.; D’Mello, S.R. Isoform-specific toxicity of MeCP2 in postmitotic neurons: Suppression of neurotoxicity by FoxG1. J. Neurosci. 2012, 32, 2846–2855.
  4. Olson, C.O.; Zachariah, R.M.; Ezeonwuka, C.D.; Liyanage, V.R.B.; Rastegar, M. Brain region-specific expression of MeCP2 isoforms correlates with DNA methylation within Mecp2 regulatory elements. PLoS ONE 2014, 9, e90645.
  5. Martínez De Paz, A.; Khajavi, L.; Martin, H.; Claveria-Gimeno, R.; Tom Dieck, S.; Cheema, M.S.; Sanchez-Mut, J.V.; Moksa, M.M.; Carles, A.; Brodie, N.I.; et al. MeCP2-E1 isoform is a dynamically expressed, weakly DNA-bound protein with different protein and DNA interactions compared to MeCP2-E2. Epigenetics Chromatin 2019, 12, 1–16.
  6. Lyst, M.J.; Ekiert, R.; Ebert, D.H.; Merusi, C.; Nowak, J.; Selfridge, J.; Guy, J.; Kastan, N.R.; Robinson, N.D.; De Lima Alves, F.; et al. Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor. Nat. Neurosci. 2013, 16, 898–902.
  7. Sharma, K.; Singh, J.; Frost, E.E.; Pillai, P.P. MeCP2 in central nervous system glial cells: Current updates. Acta Neurobiol. Exp. 2018, 78, 30–40.
  8. Sandweiss, A.J.; Brandt, V.L.; Zoghbi, H.Y. Advances in understanding of Rett syndrome and MECP2 duplication syndrome: Prospects for future therapies. Lancet Neurol. 2020, 19, 689–698.
  9. Tillotson, R.; Bird, A. The molecular basis of MeCP2 function in the brain. J. Mol. Biol. 2020, 432, 1602–1623.
  10. Bedogni, F.; Rossi, R.L.; Galli, F.; Cobolli Gigli, C.; Gandaglia, A.; Kilstrup-Nielsen, C.; Landsberger, N. Rett syndrome and the urge of novel approaches to study MeCP2 functions and mechanisms of action. Neurosci. Biobehav. Rev. 2014, 46, 187–201.
  11. Good, K.V.; Vincent, J.B.; Ausió, J. MeCP2: The genetic driver of Rett syndrome epigenetics. Front. Genet. 2021, 12, 620859.
  12. Shahbazian, M.D.; Antalffy, B.; Armstrong, D.L.; Zoghbi, H.Y. Insight into Rett syndrome: MeCP2 levels display tissue-and cell-specific differences and correlate with neuronal maturation. Hum. Mol. Genet. 2002, 11, 115–124.
  13. Kishi, N.; Macklis, J.D. MECP2 is progressively expressed in post-migratory neurons and is involved in neuronal maturation rather than cell fate decisions. Mol. Cell. Neurosci. 2004, 27, 306–321.
  14. Amir, R.E.; Van den Veyver, I.B.; Wan, M.; Tran, C.Q.; Francke, U.; Zoghbi, H. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat. Genet. 1999, 23, 185–188.
  15. Wan, M.; Sung, S.; Lee, J.; Zhang, X.; Houwink-Manville, I.; Song, H.-R.; Amir, R.E.; Budden, S.; Naidu, S.; Luiz, J.; et al. Rett Syndrome and beyond: Recurrent spontaneous and familial MECP2 mutations at CpG hotspots. Am. J. Hum. Genet 1999, 65, 1520–1529.
  16. Armstrong, J.; Póo, P.; Pineda, M.; Aibar, E.; Geán, E.; Català, V.; Nia Monrós, E. Classic Rett syndrome in a Boy as a Result of Somatic Mosaicism for a MECP2 Mutation; Wiley-Liss: Hoboken, NJ, USA, 2001.
  17. Maiwald, R.; Bönte, A.; Jung, H.; Bitter, P.; Storm, Z.; Laccone, F.; Herkenrath, P. De novo MECP2 mutation in a 46, XX male patient with Rett syndrome. Neurogenetics 2002, 4, 107–108.
  18. Lundvall, M.; Samuelsson, L.; Kyllerman, M. Male Rett phenotypes in T158M and R294X MeCP2-mutations. Neuropediatrics 2006, 37, 296–301.
  19. Psoni, S.; Sofocleous, C.; Traeger-Synodinos, J.; Kitsiou-Tzeli, S.; Kanavakis, E.; Fryssira-Kanioura, H. Phenotypic and genotypic variability in four males with MECP2 gene sequence aberrations including a novel deletion. Pediatr. Res. 2010, 67, 551–556.
  20. Neul, J.L.; Fang, P.; Barrish, J.; Lane, J.; Caeg, E.B.; Smith, E.O.; Zoghbi, H.; Percy, A.; Glaze, D.G. Specific mutations in Methyl-CpG-Binding Protein 2 confer different severity in Rett syndrome. Neurology 2008, 70, 1313–1321.
  21. Neul, J.L.; Lane, J.B.; Lee, H.S.; Geerts, S.; Barrish, J.O.; Annese, F.; Baggett, L.M.N.; Barnes, K.; Skinner, S.A.; Motil, K.J.; et al. Developmental delay in Rett syndrome: Data from the natural history study. J. Neurodev. Disord. 2014, 6, 20.
  22. Couvert, P.; Bienvenu, T.; Aquaviva, C.; Poirier, K.; Moraine, C.; Gendrot, C.; Verloes, A.; Andrès, C.; Le Fevre, A.C.; Souville, I.; et al. MECP2 is highly mutated in X-linked mental retardation. Hum. Mol. Genet. 2001, 10, 941–946.
  23. Yntema, H.G.; Kleesfstra, T.; Oudakker, A.R.; Romein, T.; de Vries, B.B.A.; Nillesen, W.; Sistermans, E.A.; Brunner, H.G.; Hamel, B.C.J.; van Bokhoven, H. Low frequency of MECP2 mutations in mentally retarded males. Eur. J. Hum. Genet. 2002, 10, 487–490.
  24. Bourdon, V.; Philippe, C.; Martin, D.; Verlò, A.; Grandemenge, A.; Jonveaux, P. MECP2 mutations or polymorphisms in mentally retarded boys diagnostic implications. Mol Diagn 2003, 7, 3–7.
  25. Moog, U.; Van Roozendaal, K.; Smeets, E.; Tserpelis, D.; Devriendt, K.; Van Buggenhout, G.; Frijns, J.P.; Schrander-Stumpel, C. MECP2 mutations are an infrequent cause of mental retardation associated with neurological problems in male patients. Brain Dev. 2006, 28, 305–310.
  26. Ravn, K.; Nielsen, J.B.; Uldall, P.; Hansen, F.J. No correlation between phenotype and genotype in boys with a truncating MECP2 mutation. J Med Genet 2003, 40, e5.
  27. Yntema, H.G.; Oudakker, A.R.; Kleefstra, T.; Hamel, B.C.J.; van Bokhoven, H.; Chelly, J.; Kalscheuer, V.M.; Fryns, J.P.; Raynaud, M.; Moizard, M.P.; et al. In-frame deletion in MECP2 causes mild nonspecific mental retardation. Am. J. Med. Genet. 2002, 107, 81–83.
  28. Bianciardi, L.; Fichera, M.; Failla, P.; Di Marco, C.; Grozeva, D.; Mencarelli, M.A.; Spiga, O.; Mari, F.; Meloni, I.; Raymond, L.; et al. MECP2 missense mutations outside the canonical MBD and TRD domains in males with intellectual disability. J. Hum. Genet. 2016, 61, 95–101.
  29. Grozeva, D.; Carss, K.; Spasic-Boskovic, O.; Parker, M.J.; Archer, H.; Firth, H.V.; Park, S.M.; Canham, N.; Holder, S.E.; Wilson, M.; et al. De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability. Am. J. Hum. Genet. 2014, 94, 618–624.
  30. Vidal, S.; Brandi, N.; Pacheco, P.; Maynou, J.; Fernandez, G.; Xiol, C.; Pascual-Alonso, A.; Pineda, M.; O’Callaghan, M.; Garcia-Cazorla, À.; et al. The most recurrent monogenic disorders that overlap with the phenotype of Rett syndrome. Eur. J. Paediatr. Neurol. 2019, 23, 609–620.
  31. Schönewolf-Greulich, B.; Bisgaard, A.M.; Dunø, M.; Jespersgaard, C.; Rokkjær, M.; Hansen, L.K.; Tsoutsou, E.; Sofokleous, C.; Topcu, M.; Kaur, S.; et al. Mosaic MECP2 variants in males with classical Rett syndrome features, including stereotypical hand movements. Clin. Genet. 2019, 95, 403–408.
  32. Sanlaville, D.; Prieur, M.; de Blois, M.C.; Genevieve, D.; Lapierre, J.M.; Ozilou, C.; Picq, M.; Gosset, P.; Morichon-Delvallez, N.; Munnich, A.; et al. Functional disomy of the Xq28 chromosome region. Eur. J. Hum. Genet. 2005, 13, 579–585.
  33. Lubs, H.; Abidi, F.; Blaymore Bier, J.-A.; Abuelo, D.; Ouzts, L.; Voeller, K.; Fennell, E.; Stevenson, R.E.; Schwartz, C.E.; Arena, F. XLMR syndrome characterized by multiple respiratory infections, hypertelorism, severe CNS deterioration and early death localizes to distal Xq28. J. Med. Genet 1999, 85, 243–248.
  34. Friez, M.J.; Jones, J.R.; Clarkson, K.; Lubs, H.; Abuelo, D.; Bier, J.A.B.; Pai, S.; Simensen, R.; Williams, C.; Giampietro, P.F.; et al. Recurrent infections, hypotonia, and mental retardation caused by duplication of MECP2 and adjacent region in Xq28. Pediatrics 2006, 118, e1687–e1695.
  35. Meins, M.; Lehmann, J.; Gerresheim, F.; Herchenbach, J.; Hagedorn, M.; Hameister, K.; Epplen, J.T. Submicroscopic duplication in Xq28 causes increased expression of the MECP2 gene in a boy with severe mental retardation and features of Rett syndrome. J. Med. Genet. 2005, 42, e12.
  36. Van Esch, H.; Bauters, M.; Ignatius, J.; Jansen, M.; Raynaud, M.; Hollanders, K.; Lugtenberg, D.; Bienvenu, T.; Jensen, L.R.; Gecz, J.; et al. Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males. Am. J. Hum. Genet. 2005, 77, 442–453.
  37. Lugtenberg, D.; Kleefstra, T.; Oudakker, A.R.; Nillesen, W.M.; Yntema, H.G.; Tzschach, A.; Raynaud, M.; Rating, D.; Journel, H.; Chelly, J.; et al. Structural variation in Xq28: MECP2 duplications in 1% of patients with unexplained XLMR and in 2% of male patients with severe encephalopathy. Eur. J. Hum. Genet. 2009, 17, 444–453.
  38. Honda, S.; Hayashi, S.; Nakane, T.; Imoto, I.; Kurosawa, K.; Mizuno, S.; Okamoto, N.; Kato, M.; Yoshihashi, H.; Kubota, T.; et al. The incidence of hypoplasia of the corpus callosum in patients with dup (X)(q28) involving MECP2 is associated with the location of distal breakpoints. Am. J. Med. Genet. Part A 2012, 158A, 1292–1303.
  39. Del Gaudio, D.; Fang, P.; Scaglia, F.; Ward, P.A.; Craigen, W.J.; Glaze, D.G.; Neul, J.L.; Patel, A.; Lee, J.A.; Irons, M.; et al. Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males. Genet. Med. 2006, 8, 784–792.
  40. Campos, M.; Churchman, S.M.; Santos-Rebouças, C.B.; Ponchel, F.; Pimentel, M.M.G. High frequency of nonrecurrent MECP2 duplications among Brazilian males with mental retardation. J. Mol. Neurosci. 2010, 41, 105–109.
  41. Lugtenberg, D.; De Brouwer, A.P.M.; Kleefstra, T.; Oudakker, A.R.; Frints, S.G.M.; Schrander-Stumpel, C.T.R.M.; Fryns, J.P.; Jensen, L.R.; Chelly, J.; Moraine, C.; et al. Chromosomal copy number changes in patients with non-syndromic X linked mental retardation detected by array CGH. J. Med. Genet. 2006, 43, 362–370.
  42. Rosenberg, C.; Knijnenburg, J.; Bakker, E.; Vianna-Morgante, A.M.; Sloos, W.; Otto, P.A.; Kriek, M.; Hansson, K.; Krepischi-Santos, A.C.V.; Fiegler, H.; et al. Array-CGH detection of micro rearrangements in mentally retarded individuals: Clinical significance of imbalances present both in affected children and normal parents. J. Med. Genet. 2006, 43, 180–186.
  43. Madrigal, I.; Rodríguez-Revenga, L.; Armengol, L.; González, E.; Rodriguez, B.; Badenas, C.; Sánchez, A.; Martínez, F.; Guitart, M.; Fernández, I.; et al. X-chromosome tiling path array detection of copy number variants in patients with chromosome X-linked mental retardation. BMC Genom. 2007, 8, 443.
  44. Bauters, M.; Van Esch, H.; Friez, M.J.; Boespflug-Tanguy, O.; Zenker, M.; Vianna-Morgante, A.M.; Rosenberg, C.; Ignatius, J.; Raynaud, M.; Hollanders, K.; et al. Nonrecurrent MECP2 duplications mediated by genomic architecture-driven DNA breaks and break-induced replication repair. Genome Res. 2008, 18, 847–858.
  45. Smyk, M.; Obersztyn, E.; Nowakowska, B.; Nawara, M.; Cheung, S.W.; Mazurczak, T.; Stankiewicz, P.; Bocian, E. Different-sized duplications of Xq28, including MECP2, in three males with mental retardation, absent or delayed speech, and recurrent infections. Am. J. Med. Genet. Part B Neuropsychiatr. Genet. 2008, 147B, 799–806.
  46. Velinov, M.; Novelli, A.; Gu, H.; Fenko, M.; Dolzhanskaya, N.; Bernardini, L.; Capalbo, A.; Dallapiccola, B.; Jenkins, E.C.; Brown, W.T. De-novo 2.15 Mb terminal Xq duplication involving MECP2 but not L1CAM gene in a male patient with mental retardation. Clin. Dysmorphol. 2009, 18, 9–12.
  47. Kirk, E.P.; Malaty-Brevaud, V.; Martini, N.; Lacoste, C.; Levy, N.; Maclean, K.; Davies, L.; Philip, N.; Badens, C. The clinical variability of the MECP2 duplication syndrome: Description of two families with duplications excluding L1CAM and FLNA. Clin. Genet. 2009, 75, 301–303.
  48. Clayton-Smith, J.; Walters, S.; Hobson, E.; Burkitt-Wright, E.; Smith, R.; Toutain, A.; Amiel, J.; Lyonnet, S.; Mansour, S.; Fitzpatrick, D.; et al. Xq28 duplication presenting with intestinal and bladder dysfunction and a distinctive facial appearance. Eur. J. Hum. Genet. 2009, 17, 434–443.
  49. Prescott, T.E.; Rødningen, O.K.; Bjørnstad, A.; Stray-Pedersen, A. Two brothers with a microduplication including the MECP2 gene: Rapid head growth in infancy and resolution of susceptibility to infection. Clin. Dysmorphol. 2009, 18, 78–82.
  50. Carvalho, C.M.B.B.; Zhang, F.; Liu, P.; Patel, A.; Sahoo, T.; Bacino, C.A.; Shaw, C.; Peacock, S.; Pursley, A.; Tavyev, J.Y.; et al. Complex rearrangements in patients with duplications of MECP2 can occur by fork stalling and template switching. Hum. Mol. Genet. 2009, 18, 2188–2203.
  51. Echenne, B.; Roubertie, A.; Lugtenberg, D.; Kleefstra, T.; Hamel, B.C.J.; Van Bokhoven, H.; Lacombe, D.; Philippe, C.; Jonveaux, P.; de Brouwer, A.P.M. Neurologic aspects of MECP2 gene duplication in male patients. Pediatr. Neurol. 2009, 41, 187–191.
  52. Ramocki, M.B.; Peters, S.U.; Tavyev, Y.J.; Zhang, F.; Carvalho, C.M.B.; Schaaf, C.P.; Richman, R.; Fang, P.; Glaze, D.G.; Lupski, J.R.; et al. Autism and other neuropsychiatric symptoms are prevalent in individuals with MECP2 duplication syndrome. Ann. Neurol. 2009, 66, 771–782.
  53. Belligni, E.F.; Palmer, R.W.; Hennekam, R.C.M. MECP2 duplication in a patient with congenital central hypoventilation. Am. J. Med. Genet. Part A 2010, 152, 1591–1593.
  54. Bartsch, O.; Gebauer, K.; Lechno, S.; Van Esch, H.; Froyen, G.; Bonin, M.; Seidel, J.; Thamm-Mücke, B.; Horn, D.; Klopocki, E.; et al. Four unrelated patients with Lubs X-linked mental retardation syndrome and different Xq28 duplications. Am. J. Med. Genet. Part A 2010, 152, 305–312.
  55. Reardon, W.; Donoghue, V.; Murphy, A.M.; King, M.D.; Mayne, P.D.; Horn, N.; Birk Møller, L. Progressive cerebellar degenerative changes in the severe mental retardation syndrome caused by duplication of MECP2 and adjacent loci on Xq28. Eur. J. Pediatr. 2010, 169, 941–949.
  56. Makrythanasis, P.; Moix, I.; Gimelli, S.; Fluss, J.; Aliferis, K.; Antonarakis, S.E.; Morris, M.A.; Béna, F.; Bottani, A. De novo duplication of MECP2 in a girl with mental retardation and no obvious dysmorphic features. Clin. Genet. 2010, 78, 175–180.
  57. Honda, S.; Hayashi, S.; Imoto, I.; Toyama, J.; Okazawa, H.; Nakagawa, E.; Goto, Y.I.; Inazawa, J. Copy-number variations on the X chromosome in Japanese patients with mental retardation detected by array-based comparative genomic hybridization analysis. J. Hum. Genet. 2010, 55, 590–599.
  58. Fernández, R.M.; Núñez-Torres, R.; González-Meneses, A.; Antiñolo, G.; Borrego, S. Novel association of severe neonatal encephalopathy and Hirschsprung disease in a male with a duplication at the Xq28 region. BMC Med. Genet. 2010, 11, 137.
  59. Jezela-Stanek, A.; Ciara, E.; Juszczak, M.; Pelc, M.; Materna-Kiryluk, A.; Krajewska-Walasek, M.; Cryptic, X. Autosome translocation in a boy—Delineation of the phenotype. Pediatr. Neurol. 2011, 44, 221–224.
  60. Breman, A.M.; Ramocki, M.B.; Kang, S.H.L.; Williams, M.; Freedenberg, D.; Patel, A.; Bader, P.I.; Cheung, S.W. MECP2 duplications in six patients with complex sex chromosome rearrangements. Eur. J. Hum. Genet. 2011, 19, 409–415.
  61. Grasshoff, U.; Bonin, M.; Goehring, I.; Ekici, A.; Dufke, A.; Cremer, K.; Wagner, N.; Rossier, E.; Jauch, A.; Walter, M.; et al. De novo MECP2 duplication in two females with random X-inactivation and moderate mental retardation. Eur. J. Hum. Genet. 2011, 19, 507–512.
  62. Budisteanu, M.; Papuc, S.M.; Tutulan-Cunita, A.; Budisteanu, B.; Arghir, A. Novel clinical finding in MECP2 duplication syndrome. Eur. Child Adolesc. Psychiatry 2011, 20, 373–375.
  63. Mayo, S.; Monfort, S.; Roselló, M.; Orellana, C.; Oltra, S.; Armstrong, J.; Català, V.; Martínez, F. De novo interstitial triplication of MECP2 in a girl with neurodevelopmental disorder and random X chromosome inactivation. Cytogenet. Genome Res. 2011, 135, 93–101.
  64. Carvalho, C.M.B.; Ramocki, M.B.; Pehlivan, D.; Franco, L.M.; Gonzaga-Jauregui, C.; Fang, P.; McCall, A.; Pivnick, E.K.; Hines-Dowell, S.; Seaver, L.H.; et al. Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome. Nat. Genet. 2011, 43, 1074–1081.
  65. Utine, G.E.; Kiper, P.Ö.; Alanay, Y.; Haliloǧlu, G.; Aktaş, D.; Boduroǧlu, K.; Tunçbilek, E.; Alikaşifoǧlu, M. Searching for copy number changes in nonsyndromic X-linked intellectual disability. Mol. Syndromol. 2012, 2, 64–71.
  66. Tang, S.S.; Fernandez, D.; Lazarou, L.P.; Singh, R.; Fallon, P. MECP2 triplication in 3 brothers—A rarely described cause of familial neurological regression in boys. Eur. J. Paediatr. Neurol. 2012, 16, 209–212.
  67. Honda, S.; Satomura, S.; Hayashi, S.; Imoto, I.; Nakagawa, E.; Goto, Y.I.; Inazawa, J. Concomitant microduplications of MECP2 and ATRX in male patients with severe mental retardation. J. Hum. Genet. 2012, 57, 73–77.
  68. Bijlsma, E.K.; Collins, A.; Papa, F.T.; Tejada, M.I.; Wheeler, P.; Peeters, E.A.J.; Gijsbers, A.C.J.; van de Kamp, J.M.; Kriek, M.; Losekoot, M.; et al. Xq28 duplications including MECP2 in five females: Expanding the phenotype to severe mental retardation. Eur. J. Med. Genet. 2012, 55, 404–413.
  69. Sanmann, J.N.; Bishay, D.L.; Starr, L.J.; Bell, C.A.; Pickering, D.L.; Stevens, J.M.; Kahler, S.G.; Olney, A.H.; Schaefer, G.B.; Sanger, W.G. Characterization of six novel patients with MECP2 duplications due to unbalanced rearrangements of the X chromosome. Am. J. Med. Genet. Part A 2012, 158A, 1285–1291.
  70. Vignoli, A.; Borgatti, R.; Peron, A.; Zucca, C.; Ballarati, L.; Bonaglia, C.; Bellini, M.; Giordano, L.; Romaniello, R.; Bedeschi, M.F.; et al. Electroclinical pattern in MECP2 duplication syndrome: Eight new reported cases and review of literature. Epilepsia 2012, 53, 1146–1155.
  71. Xu, X.; Xu, Q.; Zhang, Y.; Zhang, X.; Cheng, T.; Wu, B.; Ding, Y.; Lu, P.; Zheng, J.; Zhang, M.; et al. A case report of Chinese brothers with inherited MECP2-containing duplication: Autism and intellectual disability, but not seizures or respiratory infections. BMC Med. Genet. 2012, 13, 75.
  72. Yang, T.; Ramocki, M.B.; Neul, J.L.; Lu, W.; Roberts, L.; Knight, J.; Ward, C.S.; Zoghbi, H.Y.; Kheradmand, F.; Corry, D.B. Overexpression of methyl-CpG binding protein 2 impairs TH1 responses. Sci. Transl. Med. 2012, 4, 163ra158.
  73. Shimada, S.; Okamoto, N.; Ito, M.; Arai, Y.; Momosaki, K.; Togawa, M.; Maegaki, Y.; Sugawara, M.; Shimojima, K.; Osawa, M.; et al. MECP2 duplication syndrome in both genders. Brain Dev. 2013, 35, 411–419.
  74. Shimada, S.; Okamoto, N.; Hirasawa, K.; Yoshii, K.; Tani, Y.; Sugawara, M.; Shimojima, K.; Osawa, M.; Yamamoto, T. Clinical manifestations of Xq28 functional disomy involving MECP2 in one female and two male patients. Am. J. Med. Genet. Part A 2013, 161A, 1779–1785.
  75. Wax, J.R.; Pinette, M.G.; Smith, R.; Chard, R.; Cartin, A. Second-trimester prenasal and prefrontal skin thickening-Association with MECP2 triplication syndrome. J. Clin. Ultrasound 2013, 41, 434–437.
  76. Peters, S.U.; Hundley, R.J.; Wilson, A.K.; Carvalho, C.M.B.; Lupski, J.R.; Ramocki, M.B. Brief report: Regression timing and associated features in MECP2 duplication syndrome. J. Autism Dev. Disord. 2013, 43, 2484–2490.
  77. Scott Schwoerer, J.; Laffin, J.; Haun, J.; Raca, G.; Friez, M.J.; Giampietro, P.F. MECP2 duplication: Possible cause of severe phenotype in females. Am. J. Med. Genet. Part A 2014, 164A, 1029–1034.
  78. Novara, F.; Simonati, A.; Sicca, F.; Battini, R.; Fiori, S.; Contaldo, A.; Criscuolo, L.; Zuffardi, O.; Ciccone, R. MECP2 duplication phenotype in symptomatic females: Report of three further cases. Mol. Cytogenet. 2014, 7, 10.
  79. Fukushi, D.; Yamada, K.; Nomura, N.; Naiki, M.; Kimura, R.; Yamada, Y.; Kumagai, T.; Yamaguchi, K.; Miyake, Y.; Wakamatsu, N. Clinical characterization and identification of duplication breakpoints in a Japanese family with Xq28 duplication syndrome including MECP2. Am. J. Med. Genet. Part A 2014, 164A, 924–933.
  80. Bauer, M.; Kölsch, U.; Krüger, R.; Unterwalder, N.; Hameister, K.; Kaiser, F.M.; Vignoli, A.; Rossi, R.; Botella, M.P.; Budisteanu, M.; et al. Infectious and immunologic phenotype of MECP2 Duplication syndrome. J. Clin. Immunol. 2015, 35, 168–181.
  81. Miyatake, S.; Koshimizu, E.; Fujita, A.; Fukai, R.; Imagawa, E.; Ohba, C.; Kuki, I.; Nukui, M.; Araki, A.; Makita, Y.; et al. Detecting copy-number variations in whole-exome sequencing data using the exome hidden markov model: An “exome-first” approach. J. Hum. Genet. 2015, 60, 175–182.
  82. Trobaugh-Lotrario, A.; Martin, J.; López-Terrada, D. Hepatoblastoma in a male with MECP2 duplication syndrome. Am. J. Med. Genet. Part A 2016, 170A, 790–791.
  83. Zhang, Q.; Zhao, Y.; Yang, Y.; Bao, X. MECP2 duplication syndrome in a Chinese family. BMC Med. Genet. 2015, 16, 112.
  84. El Chehadeh, S.; Faivre, L.; Mosca-Boidron, A.L.; Malan, V.; Amiel, J.; Nizon, M.; Touraine, R.; Prieur, F.; Pasquier, L.; Callier, P.; et al. Large national series of patients with Xq28 duplication involving MECP2: Delineation of brain MRI abnormalities in 30 affected patients. Am. J. Med. Genet. Part A 2016, 170A, 116–129.
  85. Nageshappa, S.; Carromeu, C.; Trujillo, C.A.; Mesci, P.; Espuny-Camacho, I.; Pasciuto, E.; Vanderhaeghen, P.; Verfaillie, C.M.; Raitano, S.; Kumar, A.; et al. Altered neuronal network and rescue in a human MECP2 duplication model. Mol. Psychiatry 2016, 21, 178–188.
  86. Signorini, C.; De Felice, C.; Leoncini, S.; Møller, R.S.; Zollo, G.; Buoni, S.; Cortelazzo, A.; Guerranti, R.; Durand, T.; Ciccoli, L.; et al. MECP2 duplication syndrome: Evidence of enhanced oxidative stress. A comparison with Rett syndrome. PLoS ONE 2016, 11, e0150101.
  87. Yi, Z.; Pan, H.; Li, L.; Wu, H.; Wang, S.; Ma, Y.; Qi, Y. Chromosome Xq28 duplication encompassing MECP2: Clinical and molecular analysis of 16 new patients from 10 families in China. Eur. J. Med. Genet. 2016, 59, 347–353.
  88. San Antonio-Arce, V.; Fenollar-Cortés, M.; Ionescu, R.O.; DeSantos-Moreno, T.; Gallego-Merlo, J.; Cámara, F.J.I.; Pérez, M.C.O. MECP2 Duplications in symptomatic females. Child Neurol. Open 2016, 3.
  89. Tsuji-Hosokawa, A.; Matsuda, N.; Kurosawa, K.; Kashimada, K.; Morio, T. A case of MECP2 duplication syndrome with gonadotropin-dependent precocious puberty. Horm. Res. Paediatr. 2017, 87, 271–276.
  90. Ha, K.; Shen, Y.; Graves, T.; Kim, C.H.; Kim, H.G. The presence of two rare genomic syndromes, 1q21 deletion and Xq28 duplication, segregating independently in a family with intellectual disability. Mol. Cytogenet. 2016, 9, 74.
  91. Lim, Z.; Downs, J.; Wong, K.; Ellaway, C.; Leonard, H. Expanding the clinical picture of the MECP2 Duplication syndrome. Clin. Genet. 2017, 91, 557–563.
  92. El Chehadeh, S.; Touraine, R.; Prieur, F.; Reardon, W.; Bienvenu, T.; Chantot-Bastaraud, S.; Doco-Fenzy, M.; Landais, E.; Philippe, C.; Marle, N.; et al. Xq28 duplication including MECP2 in six unreported affected females: What can we learn for diagnosis and genetic counselling? Clin. Genet. 2017, 91, 576–588.
  93. Moirangthem, A.; Tuteja Bhatia, M.; Srivastava, P.; Mandal, K.; Rai, A.; Phadke, S.R. Expansion of the phenotypic spectrum in three families of methyl CpG-binding protein 2 duplication syndrome. Clin. Dysmorphol. 2017, 26, 73–77.
  94. Yon, D.K.; Park, J.E.; Kim, S.J.; Shim, S.H.; Chae, K.Y. A sibship with duplication of Xq28 inherited from the mother; genomic characterization and clinical outcomes. BMC Med. Genet. 2017, 18, 1–9.
  95. Li, X.; Xie, H.; Chen, Q.; Yu, X.; Yi, Z.; Li, E.; Zhang, T.; Wang, J.; Zhong, J.; Chen, X. Clinical and molecular genetic characterization of familial MECP2 duplication syndrome in a Chinese family. BMC Med. Genet. 2017, 18, 131.
  96. Deshwar, A.R.; Dupuis, L.; Bergmann, C.; Stavropoulos, J.; Mendoza-Londono, R. Severe rhizomelic shortening in a child with a complex duplication/deletion rearrangement of chromosome X. Am. J. Med. Genet. Part A 2018, 176A, 450–454.
  97. Bauer, M.; Krüger, R.; Kölsch, U.; Unterwalder, N.; Meisel, C.; Wahn, V.; Von Bernuth, H. Antibiotic prophylaxis, immunoglobulin substitution and supportive measures prevent infections in MECP2 duplication syndrome. Pediatr. Infect. Dis. J. 2018, 37, 466–468.
  98. Miguet, M.; Faivre, L.; Amiel, J.; Nizon, M.; Touraine, R.; Prieur, F.; Pasquier, L.; Lefebvre, M.; Thevenon, J.; Dubourg, C.; et al. Further delineation of the MECP2 duplication syndrome phenotype in 59 French male patients, with a particular focus on morphological and neurological features. J. Med. Genet. 2018, 55, 359–371.
  99. Pitzianti, M.B.; Palombo, A.S.; Esposito, S.; Pasini, A. Rett syndrome in males: The different clinical course in two brothers with the same microduplication MECP2 Xq28. Int. J. Environ. Res. Public Health 2019, 16, 3075.
  100. Kanai, S.; Okanishi, T.; Fujimoto, A.; Itamura, S.; Baba, S.; Nishimura, M.; Itomi, K.; Enoki, H. Successful corpus callosotomy for post-encephalopathic refractory epilepsy in a patient with MECP2 duplication syndrome. Brain Dev. 2019, 41, 296–300.
  101. Marafi, D.; Suter, B.; Schultz, R.; Glaze, D.; Pavlik, V.N.; Goldman, A.M. Spectrum and time course of epilepsy and the associated cognitive decline in MECP2 duplication syndrome. Neurology 2019, 92, E108–E114.
  102. Lotti, F.; Geronzi, U.; Grosso, S. Electroencephalographic and epilepsy findings in mecp2 duplication syndrome. A family study. Brain Dev. 2019, 41, 456–459.
  103. Giudice-Nairn, P.; Downs, J.; Wong, K.; Wilson, D.; Ta, D.; Gattas, M.; Amor, D.; Thompson, E.; Kirrali-Borri, C.; Ellaway, C.; et al. The incidence, prevalence and clinical features of MECP2 duplication syndrome in Australian children. J. Paediatr. Child Health 2019, 55, 1315–1322.
  104. Peters, S.U.; Fu, C.; Suter, B.; Marsh, E.; Benke, T.A.; Skinner, S.A.; Lieberman, D.N.; Standridge, S.; Jones, M.; Beisang, A.; et al. Characterizing the phenotypic effect of Xq28 duplication size in MECP2 duplication syndrome. Clin. Genet. 2019, 95, 575–581.
  105. Pascual-Alonso, A.; Blasco, L.; Vidal, S.; Gean, E.; Rubio, P.; O’Callaghan, M.; Martínez-Monseny, A.F.; Castells, A.A.; Xiol, C.; Català, V.; et al. Molecular characterization of Spanish patients with MECP2 duplication syndrome. Clin. Genet. 2020, 97, 610–620.
  106. Gutiérrez-Sánchez, A.M.; Marín-Andrés, M.; López-Lafuente, A.; Monge-Galindo, L.; López-Pisón, J.; Peña-Segura, J.L. Síndrome de duplicación MECP2 familiar. Rev. Neurol. 2020, 70, 309–310.
  107. Cutri-French, C.; Armstrong, D.; Saby, J.; Gorman, C.; Lane, J.; Fu, C.; Peters, S.U.; Percy, A.; Neul, J.L.; Marsh, E.D. Comparison of core features in four developmental encephalopathies in the Rett Natural History Study. Ann. Neurol. 2020, 88, 396–406.
  108. Choi, Y.L.J.; Wong, T.K.M.; Ng, K.K.D. Anesthetic management for a patient with MECP2 duplication syndrome: A case report. A&A Pract. 2020, 14, e01202.
  109. van Baelen, A.; Verhoustraeten, L.; Kenis, S.; Meuwissen, M.; Boudewyns, A.; van Hoorenbeeck, K.; Verhulst, S. Sleep-disordered breathing and nocturnal hypoventilation in children with the MECP2 duplication syndrome: A case series and review of the literature. Am. J. Med. Genet. Part A 2020, 182A, 2437–2441.
  110. Tekendo-Ngongang, C.; Dahoun, S.; Nguefack, S.; Moix, I.; Gimelli, S.; Zambo, H.; Morris, M.A.; Sloan-Béna, F.; Wonkam, A. MECP2 duplication syndrome in a patient from Cameroon. Am. J. Med. Genet. Part A 2020, 182, 619–622.
  111. Peters, S.U.; Fu, C.; Marsh, E.D.; Benke, T.A.; Suter, B.; Skinner, S.A.; Lieberman, D.N.; Standridge, S.; Jones, M.; Beisang, A.; et al. Phenotypic features in MECP2 duplication syndrome: Effects of age. Am. J. Med. Genet. Part A 2021, 185A, 362–369.
  112. Takeguchi, R.; Takahashi, S.; Akaba, Y.; Tanaka, R.; Nabatame, S.; Kurosawa, K.; Matsuishi, T.; Itoh, M. Early diagnosis of MECP2 duplication syndrome: Insights from a nationwide survey in Japan. J. Neurol. Sci. 2021, 422, 117321.
  113. Al Ali, A.; Singh, R.; Filler, G. Abdominal compartment syndrome secondary to chronic constipation in MECP2 duplication syndrome. Clin. Care Med. 2021, 49, 291.
  114. Ip, J.P.K.; Mellios, N.; Sur, M. Rett syndrome: Insights into genetic, molecular and circuit mechanisms. Nat. Rev. Neurosci. 2018, 19, 368–382.
  115. Heckman, L.D.; Chahrour, M.H.; Zoghbi, H.Y. Rett-causing mutations reveal two domains critical for MeCP2 function and for toxicity in MECP2 duplication syndrome mice. Elife 2014, 3, e02676.
  116. Shao, Y.; Sztainberg, Y.; Wang, Q.; Bajikar, S.S.; Trostle, A.J.; Wan, Y.-W.; Jafar-Nejad, P.; Rigo, F.; Liu, Z.; Tang, J.; et al. Antisense oligonucleotide therapy in a humanized mouse model of MECP2 duplication syndrome. Sci. Transl. Med 2021, 13, 7785.
  117. Wojtal, D.; Kemaladewi, D.U.; Malam, Z.; Abdullah, S.; Wong, T.W.Y.; Hyatt, E.; Baghestani, Z.; Pereira, S.; Stavropoulos, J.; Mouly, V.; et al. Spell Checking Nature: Versatility of CRISPR/Cas9 for Developing Treatments for Inherited Disorders. Am. J. Hum. Genet. 2016, 98, 90–101.
  118. Tang, X.; Kim, J.; Zhou, L.; Wengert, E.; Zhang, L.; Wu, Z.; Carromeu, C.; Muotri, A.R.; Marchetto, M.C.N.; Gage, F.H.; et al. KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome. Proc. Natl. Acad. Sci. USA 2016, 113, 751–756.
  119. Tang, X.; Drotar, J.; Li, K.; Clairmont, C.D.; Brumm, A.S.; Sullins, A.J.; Wu, H.; Liu, S.; Wang, J.; Gray, N.S.; et al. Pharmacological enhancement of KCC2 gene expression exerts therapeutic effects on human Rett syndrome neurons and Mecp2 mutant mice. Sci. Transl. Med 2019, 11, eaau0164.
  120. Kim, J.J.; Savas, J.N.; Miller, M.T.; Hu, X.; Carromeu, C.; Lavallée-Adam, M.; Freitas, B.C.G.; Muotri, A.R.; Yates, J.R.; Ghosh, A. Proteomic analyses reveal misregulation of LIN28 expression and delayed timing of glial differentiation in human iPS cells with MECP2 loss-of-function. PLoS ONE 2019, 14, e0212553.
  121. Gomes, A.R.; Fernandes, T.G.; Cabral, J.M.S.; Diogo, M.M. Modeling rett syndrome with human pluripotent stem cells: Mechanistic outcomes and future clinical perspectives. Int. J. Mol. Sci. 2021, 22, 3751.
  122. Gomes, A.R.; Fernandes, T.G.; Vaz, S.H.; Silva, T.P.; Bekman, E.P.; Xapelli, S.; Duarte, S.; Ghazvini, M.; Gribnau, J.; Muotri, A.R.; et al. Modeling Rett syndrome with human patient-specific forebrain organoids. Front. Cell Dev. Biol. 2020, 8, 610427.
  123. Ash, R.T.; Park, J.; Suter, B.; Smirnakis, S.M.; Zoghbi, H.Y. Excessive formation and stabilization of dendritic spine clusters in the mecp2-duplication syndrome mouse model of autism. eNeuro 2021, 8, 1–13.
  124. Ash, R.T.; Buffington, S.A.; Park, J.; Suter, B.; Costa-Mattioli, M.; Zoghbi, H.Y.; Smirnakis, S.M. Inhibition of elevated ras-mapk signaling normalizes enhanced motor learning and excessive clustered dendritic spine stabilization in the mecp2-duplication syndrome mouse model of autism. eNeuro 2021, 8.
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