Vol. 30-31/2021-2022 Nr 60
okładka czasopisma Child Neurology
powiększenie okładki
Informacje o Pismie

NEUROLOGIA DZIECIĘCA

Pismo Polskiego Towarzystwa Neurologów Dziecięcych

PL ISSN 1230-3690
e-ISSN 2451-1897
DOI 10.20966
Półrocznik


Powrót

Zespół Retta – postępy badań nad patogenezą


Rett Syndrome – progress of research on pathogenesis




Zakład Genetyki Klinicznej, Uniwersytetu Medycznego w Białymstoku

Neurol Dziec 2010; 19, 38: 55-63
Pełen tekst artykułu PDF Zespół Retta – postępy badań nad patogenezą



STRESZCZENIE
Zespół Retta (RTT) jest neurorozwojowym schorzeniem uwarunkowanym genetycznie, które charakteryzuje się współwystępowaniem szeregu objawów klinicznych, głównie ze strony układu nerwowego, układu pokarmowego i kostnego. Zaburzenia powstają jako wynik mutacji genu MECP2 z locus geni w Xq28, a w sporadycznych przypadkach na skutek mutacji innych genów: CDKL5 (STK9), NTNG, MEF2C lub FOXG1. Patogeneza RTT jest związana z nieprawidłową funkcją MeCP2, czynnika transkrypcyjnego działającego na geny docelowe w zależności od potrzeb homeostazy neuronalnej albo jako represor ich transkrypcji albo jako aktywator. Białko MeCP2 kontroluje wiele szlaków sygnałowych białek i przywrócenie ich funkcji może być wykorzystane do opracowania sposobów leczenia poszczególnych zaburzeń składających się na fenotyp RTT.

Słowa kluczowe: zespół Retta, MECP2, białko MeCP2, geny docelowe.


ABSTRACT
Rett syndrome (RTT) belongs to neurodevelopmental genetic disorders, which is characterised by a number of traits, mainly from neurological, gastro-intestinal and skeletal systems. This disorder is caused by MECP2 mutations in locus geni at Xq28 and sporadically due to mutations of other genes CDKL5 (STK9), NTNG1, MEF2C or FOXG1. Pathogenesis of RTT is connected with malfunctions of MeCP2 protein acting according to the needs of actual neuronal homeostasis as transcription repressor or as an activator of different target genes. MeCP2 protein controls many signalling pathways and uncovering their disturbances opens new possibilities for treatment in particular abnormalities of RTT phenotype.

Key words: Rett syndrome, MECP2, MeCP2 protein, target genes.


PIŚMIENNICTWO
[1] 
Hagberg B., Aicardi J., Dias K., et al.: A progressive syndrome of autism dementia ataxia and loss of purposeful hand use in girls: Rett’s syndrome: report of 35 cases. Ann Neurol 1983; 14: 471-479.
[2] 
Online Mendelian Inheritance in Man .www.ncbi.nlm.nih.gov/omim/
[3] 
Midro A.T.: Genetyczne podłoże zespołu Retta – gen MECP2. Neurol Dziec 2001; 10: 71-83.
[4] 
Midro A.T.: Poradnictwo genetyczne w zespole Retta. Część I. Diagnoza fenotypowa i molekularna. Przegl Ped 2002; 32 (2): 98-103.
[5] 
Midro A.T.: Poradnictwo genetyczne w zespole Retta. Część II. Problemy psychologiczne i prognoza rozwoju. Przegl Ped 2002; 32 (2): 158-162.
[6] 
Uścińska E., Skawrońska M., Midro A.T.: Poradnictwo genetyczne w z. Retta. Część III. Korelacja genotypowo-fenotypowa. Przegl Ped 2005; 35 (1): 41-49.
[7] 
Midro A.T., Midro H.: Czy dialog genów ze środowiskiem może kształtować fenotyp zachowania w zespole Retta i innych zaburzeniach? Psych Pol 2006; 11 (5): 949-967.
[8] 
Midro A.T.: Nie tylko genetyczne uwarunkowanie zespołu Retta. Autyzm 2006; 5: 22-27.
[9] 
Midro A. T., Haus O., Kobel-Buys K. et al.: Możliwości wspomagania rozwoju dzieci z zespołami uwarunkowanymi genetycznie. Doświadczenia z corocznych spotkań integracyjnych. [w:] W drodze do brzegu życia. Krajewska-Kułak E., Nyklewicz W., Łukaszuk C. (red.), Uniwersytet Medyczny, Białystok 2008, V, 315-329.
[10] 
Midro A.T., Posmyk R.: Poradnictwo genetyczne w zespole Retta. Część IV. Udział rodziców. Przegl Ped 2009; 39 (3): 193-199.
[11] 
Midro A.T.: Schorzenia uwarunkowane genetycznie ze szczególnym uwzględnieniem schorzeń genomowych. [w:] Pediatria – co nowego? Otto-Buczkowska E. (red.), Cornetis, Wrocław 2007, 361-369.
[12] 
Midro A.T.: Śmierć społeczna w praktyce genetyki klinicznej. [w:] W drodze do brzegu życia. Krajewska-Kułak E., Nyklewicz W., Łukaszuk C. (red.), Uniwersytet Medyczny, Białystok 2007, III, 399-408.
[13] 
Midro A.T.: Nie tylko genetyczne uwarunkowanie zespołu Retta. Autyzm 2006; 5: 22-27.
[14] 
Zoghbi H.Y.: Postnatal neurodevelopmental disorders: meeting at the synapse? Science 2003; 302: 826–830.
[15] 
Williamson S.L., Christodoulou J.: Rett syndrome: new clinical and molecular insights. Eur J Hum Genet. 2006; 14 (8): 896-903.
[16] 
Chahrour M., Zoghbi H.Y.: The Story of Rett Syndrome: From Clinic to Neurobiology. Neuron 2007; 56 (3): 422-437.
[17] 
Mount R.H., Hastings R.P., Reilly S. et al.: Behavioural and emotional features in Rett syndrome. Disabil Rehabil 2001; 23: 129–138.
[18] 
Nomura Y.: Early behavior characteristics and sleep disturbance in Rett syndrome. Brain Dev 2005; 27 (1): 35–42.
[19] 
Weese-Mayer D.E., Lieske S.P., Boothby C.M. et al.: Autonomic nervous system dysregulation: breathing and heart rate perturbation during wakefulness in young girls with Rett syndrome. Pediatr Res 2006; 60: 443–449.
[20] 
Jian L., Nagarajan L., de Klerk N. et al.: Predictors of seizure onset in Rett syndrome. J Pediatr 2006; 49: 542–547.
[21] 
Hagberg B.: Rett syndrome: long-term clinical follow-up experiences over four decades J Child Neurol 2005; 20: 722–727.
[22] 
Roze E., Cochen V., Sangla S. et al.: Rett syndrome: An overlooked diagnosis in women with stereotypic hand movements psychomotor retardation Parkinsonism and dystonia? Mov Disord 2007; 22: 387– 389.
[23] 
Ogier M., Katz D.M.: Breathing dysfunction in Rett syndrome: Understanding epigenetic regulation of the respiratory network. Respir Physiol Neurobiol 2008; 164: 55–63.
[24] 
Moser S.J., Weber P., Lutschg J.: Rett syndrome: clinical and electrophysiologic aspects. Pediatr Neurol 2007; 36: 95–100.
[25] 
Glaze D.G.: Neurophysiology of Rett syndrome J. Child Neurol 2005; 20: 740–746.
[26] 
Chahrour M., Zoghbi H.Y.: The story of Rett syndrome: from clinic to neurobiology. Neuron 2007; 56 (3): 422-437.
[27] 
Amir R.E., Van D.V., Wan M. et. al.: Rett syndrome is caused by mutation in X-linked MECP2, encoding metyl-CpG-binding protein 2. Nat Genet 1999; 23: 185-188.
[28] 
Venancio M., Santos M., Pereira S.A. et al.: An explanation for another familial case of Rett syndrome: maternal germline mosaicism. Europ J. Hum Genet 2007; 15: 902-904.
[29] 
Gill H., Cheadle J.P., Maynard J. et al.: Mutation analysis in the MECP2 gene and genetic counselling for Rett syndrome. J Med Genet 2003; 40: 380-384.
[30] 
Evans J.C., Archer H.L., Whatley S.D. et al.: Germline mosaicism for a MECP2 mutation in a man with two Rett daughters. Clin Genet 2006; 70 (4): 336-338.
[31] 
Villard L., Lévy N., Xiang F. et al.: Segregation of a totally skewed pattern of X chromosome inactivation in four familial cases of Rett syndrome without MECP2 mutation: implications for the disease. J Med Genet 2001; 38 (7): 435-442.
[32] 
Quaderi N.A., Meehan R.R., Tate P.H. et al.: Genetic and physical mapping of a gene encoding a methyl CpG binding protein Mecp2, to the mouse X chromosome. Genomics 1994; 22: 648-651.
[33] 
D’Esposito M., Quaderi N.A., Ciccodicola A. et al.: Isolation physical mapping and northern analysis of the X-linked human gene encoding methyl CpG-binding protein MECP2. Mamm Genome 1996; 7: 533–535.
[34] 
Singh J., Saxena A., Christodoulou J. et al.: MECP2 genomic structure and function: insights from ENCODE. Nucleic Acids Res 2008; 36(19): 6035-6047.
[35] 
Jurkiewicz D., Popowska E., Tylki-Szymańska A. et al.: Molekularne mechanizmy powstawania zespołu Retta. Post Biol Kom 2006; 33 (2): 186-196.
[36] 
Djarmati A., Dobricic V, Kecmanovi M. et al.: MECP2 mutations in Serbian Rett syndrome patients. Acta Neurol Scand 2007; 116: 413-419.
[37] 
Matijevic T., Knezevic J., Slavica M. et al.: Rett Syndrome: From the Gene to the Disease. Eur Neurol 2008; 61 (1): 3-10.
[38] 
Ariani F., Mari F., Pescucci C. et al.: Real-time quantitative PCR as a routine method for screening large rearrangements in Rett syndrome: Report of one case of MECP2 deletion and one case of MECP2 duplication. Hum Mutat 2004; 24: 172–177.
[39] 
Friez M.J., Jones J.R., Clarkson K. et al.: Recurrent infections hypotonia and mental retardation caused by duplication of MECP2 and adjacent region in Xq28. Pediatrics 2006; 118: 1687–1695.
[40] 
Lugtenberg D., de Brouwer A.P., Kleefstra T. 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.
[41] 
Meins M., Lehmann J., Gerresheim F. et al.: 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: 12.
[42] 
Van Esch H., Bauters M., Ignatius 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.
[43] 
Gonzales M.L., LaSalle J.M.: The role of MeCP2 in brain development and neurodevelopmental disorders. Curr Psychiatry Rep 2010; 2: 127- 134.
[44] 
Bourdon V., Philippe C., Bienvenu T.et al.: Evidence of somatic mosaicism for a MECP2 mutation in females with Rett syndrome: diagnostic implications. J Med Genet 2001; 38: 867-871.
[45] 
Huppke P., Maier E. M., Warnke A. et al.: Very mild cases of Rett syndrome with skewed X inactivation. J Med Genet 2006; 43: 814-816.
[46] 
Dragich J., Houwink-Manville C., Schanen N. et al.: Rett syndrome: a surprising result of mutation in MECP2. Hum Mol Genet 2000; 9: 2365- 2375.
[47] 
Young I., Zoghbi H.Y.: X-chromosome inactivation patterns are unbalanced and affect the phenotypic outcome in a mouse model of rett syndrome. Am J Hum Genet 2004; 74: 511–520.
[48] 
Scala E., Longo I., Ottimo F. et al.: MECP2 deletions and genotypephenotype correlation in Rett syndrome. Am J Med Genet A 2007; 143: 2775-2784.
[49] 
Takahashi S., Ohinata J., Makita Y., et al.: Skewed X chromosome inactivation failed to explain the normal phenotype of a carrier female with MECP2 mutation resulting in Rett syndrome. Clin Genet 2008; 73: 257-261.
[50] 
Xinhua B., Shengling J., Fuying S. et al.: X chromosome inactivation in Rett syndrome and its correlations with MECP2 mutations and phenotype. J Child Neurol 2008; 23: 22-25.
[51] 
Mari F., Azimonti S., Bertani I. et al.: CDKL5 belongs to the same molecular pathway of MeCP2 and it is responsible for the early-onset seizure variant of Rett syndrome. Hum Mol Genet 2005; 14: 1935-1946.
[52] 
Bertani I., Rusconi L., Bolognese F. et al.: Functional consequences of mutations in CDKL5, an X linked gene involved in infantile spasms and mental retardation. J Biol Chem 2006; 281: 32048-32056.
[53] 
Weaving L.S., Christodoulou J., Williamson S.L. et al.: Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation. Am J Hum Genet 2004; 75: 1079- 1093.
[54] 
Tao J., Van Esch H., Hagedorn-Greiwe M. et al.: Mutations in the Xlinked cyclin-dependent kinase-like 5 (CDKL5/ STK9) gene are associated with severe neurodevelopmental retardation. Am J Hum Genet 2004; 75: 1149-1154.
[55] 
Shoichet S.A., Kunde S.A., Viertel P. et al.: Haploinsufficiency of novel FOXG1B variants in a patient with severe mental retardation brain malformations and microcephaly. Hum Genet 2005; 117: 536-544.
[56] 
Ariani F., Hayek G., Rondinella D. et al.: FOXG1 is responsible for the congenital variant of Rett syndrome. Am J Hum Genet 2008; 83: 89-93.
[57] 
Zweier M., Gregor A., Zweier C. et al.: Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression. Hum Mutat 2010; 31: 722-733.
[58] 
Borg I., Freude K., Kübart S. et al.: Disruption of Netrin G1 by a balanced chromosome translocation in a girl with Rett syndrome. Eur J Hum Genet 2005; 13: 921-927.
[59] 
Archer H.L., Evans J.C., Millar D.S. et al.: NTNG1 mutations are a rare cause of Rett syndrome. Am J Med Genet A 2006; 140: 691-694.
[60] 
Chahrour M., Zoghbi HY.: The story of Rett syndrome: from clinic to neurobiology. Neuron 2007; 56 (3): 422-437.
[61] 
Chahrour M., Jung S.Y., Shaw C. et al.: MeCP2, a key contributor to neurological disease activates and represses transcription. Science 2008; 320 (5880): 1224-1229.
[62] 
Chen W.G., Chang Q., Lin Y. et al.: Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science 2003; 302: 885-889.
[63] 
Zhou Z., Hong E.J., Cohen S. et al.: Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron 2006; 52 (2): 255-269.
[64] 
Flavell S.W., Greenberg M.E.: Signaling mechanisms linking neuronal activity to gene expression and plasticity of the nervous system. Annu Rev Neurosci 2008; 31: 563-590.
[65] 
Smrt R.D., Eaves-Egenes J., Barkho B.Z. et al.: Mecp2 deficiency leads to delayed maturation and altered gene expression in hippocampal neurons. Neurobiol Dis 2007; 27: 77-89.
[66] 
Asaka Y., Jugloff D.G., Zhang L. et al.: Hippocampal synaptic plasticity is impaired in the Mecp2-null mouse model of Rett syndrome. Neurobiol Dis 2006; 21: 217-227.
[67] 
Belichenko P.V., Dahlstrom A.: Studies on the 3-dimensional architecture of dendritic spines and varicosities in human cortex by confocal laser scanning microscopy and Lucifer yellow microinjections. J Neurosci Methods 1995; 57: 55-61.
[68] 
Armstrong D.D.: Neuropathology of Rett syndrome. Ment Retard Dev Disabil Res Rev 2002; 8: 72-76.
[69] 
Kishi N., Macklis J.D.: MECP2 is progressively expressed in postmigratory neurons and is involved in neuronal maturation rather than cell fate decisions. Mol Cell Neurosci 2004; 27: 306-321.
[70] 
Kline D.D., Ogier M., Kunze D.L. et al.: Exogenous brain-derived neurotrophic factor rescues synaptic dysfunction in mecp2-null mice. J Neuroscience 2010; 30 (15): 5303-5310.
[71] 
Tropea D., Giacometti E., Wilson N.R. et al.: Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice. Proc Natl Acad Sci USA 2009; 106 (6): 2029-2034.
[72] 
Marcus C.L., Carroll J.L., McColley S.A. et al.: Polysomnographic characteristics of patients with Rett syndrome. J Pediatr 1994; 125: 218-224.
[73] 
Julu P.O., Kerr A.M., Apartopoulos F. et al.: Characterisation of breathing and associated central autonomic dysfunction in the Rett disorder. Arch Dis Child 2001; 85: 29-37.
[74] 
Stettner G.M., Huppke P., Brendel C. et al.: Breathing dysfunctions associated with impaired control of postinspiratory activity in Mecp2_/y knockout mice. J Physiol 2007; 579: 863-876.
[75] 
Viemari J.C., Roux J.C., Tryba A.K. et al.: Mecp2 deficiency disrupts norepinephrine and respiratory systems in mice. J Neurosci 2005; 25: 11521-11530.
[76] 
Chang Q., Khare G., Dani V. et al.: The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression. Neuron 2006; 49: 341-348.
[77] 
Wang H., Chan S.A., Ogier M. et al.: Dysregulation of brain-derived neurotrophic factor expression and neurosecretory function in Mecp2 null mice. J Neurosci 2006; 26: 10911-10915.
[78] 
Katz D.M.: Regulation of respiratory neuron development by neurotrophic and transcriptional signaling mechanisms. Respir Physiol Neurobiol 2005; 149: 99-109.
[79] 
Baker-Herman T.L., Fuller D.D., Bavis R.W. et al.: BDNF is necessary and sufficient for spinal respiratory plasticity following intermittent hypoxia. Nat Neurosci 2004; 7: 48-55.
[80] 
Wilkerson J.E., Mitchell G.S.: Daily intermittent hypoxia augments spinal BDNF levels, ERK phosphorylation and respiratory long-term facilitation. Exp Neurol 2009; 217 (1): 116-123.
[81] 
De Felice C., Ciccoli L., Leoncini S. et al.: Systemic oxidative stress in classic Rett syndrome. Free Radic Biol Med 2009; 47 (4 ): 440-448.
[82] 
Ogier M., Wang H., Hong E. et al.: Brain-Derived Neurotrophic Factor Expression and Respiratory Function Improve after Ampakine Treatment in a Mouse Model of Rett Syndrome. J Neurosci 2007; 27 (40): 10912- 10917.
[83] 
Lauterborn J.C., Lynch G., Vanderklish P. et al.: Positive modulation of AMPA receptors increases neurotrophin expression by hippocampal and cortical neurons. J Neurosci 2000; 20: 8-21.
[84] 
Lauterborn J.C., Truong G.S., Baudry M. et al.: Chronic elevation of brainderived neurotrophic factor by ampakines. J Pharmacol Exp Ther 2003; 307: 297-305.
[85] 
Rex C.S., Lauterborn J.C., Lin C.Y. et al.: Restoration of long-term potentiation in middle-aged hippocampus after induction of brain-derived neurotrophic factor. J Neurophysiol 2006; 96: 677-685.
[86] 
Wezenberg E., Jan Verkes R., Ruigt G.S. et al.: Acute effects of the ampakine farampator on memory and information processing in healthy elderly volunteers. Neuropsychopharmacology 2006; 32: 1272-1283.
[87] 
Balkowiec A., Kunze D.L., Katz D.M.: Brain-derived neurotrophic factor acutely inhibits AMPA-mediated currents in developing sensory relay neurons. J Neurosci 2000; 20: 1904-1911.
[88] 
Roux J.C., Dura E., Moncla A. et al.: Treatment with desipramine improves breathing and survival in a mouse model for Rett syndrome. Eur J Neurosci 2007; 25 (7): 1915-1919.
[89] 
Zanella S., Mebarek S., Lajard A.M. et al.: Oral treatment with desipramine improves breathing and life span in Rett syndrome mouse model. Respir Physiol Neurobiol 2008; 160 (1): 116-121.
[90] 
Kerr A.M.: A review of the respiratory disorder in the Rett syndrome. Brain Dev 1992; 14: 43-45.
[91] 
Woodyatt G.C., Murdoch B.E.: The effect of the presentation of visual and auditory stimuli on the breathing patterns of two girls with Rett syndrome. Intellect Disabil Res 1996; 40: 252-259.
[92] 
Nuber U.A., Kriaucionis S., Roloff T.C. et al.: Up-regulation of glucocorticoid-regulated genes in a mouse model of Rett syndrome. Hum Mol Genet 2005; 14: 2247-2256.
[93] 
McGill B.E., Bundle S.F., Yaylaoglu M.B. et al.: Enhanced anxiety and stress-induced corticosterone release are associated with increased Crh expression in a mouse model of Rett syndrome. Proc Natl Acad Sci USA 2006; 103: 18267-18272.
[94] 
Fyffe S.L., Neul J.L., Samaco R.C. et al.: Deletion of Mecp2 in Sim1- expressing neurons reveals a critical role for MeCP2 in feeding behavior aggression and the response to stress. Neuron 2008; 59 (6): 947-958.
[95] 
Deng V., Matagne V., Banine F. et al.: FXYD1 is an MeCP2 target gene overexpressed in the brains of Rett syndrome patients and Mecp2-null mice. Hum Mol Genet 2007; 16 (6): 640-650.
[96] 
Horike S., Cai S., Miyano M. et al.: Loss of silent-chromatin looping and impaired imprinting of DLX5 in Rett syndrome. Nat Genet 2005; 37: 31- 40.
[97] 
Itoh M., Ide S., Takashima S. et al.: Methyl CpG-binding protein 2 (a mutation of which causes Rett syndrome) directly regulates insulinlike growth factor binding protein 3 in mouse and human brains. J Neuropathol Exp Neurol 2007; 66 (2): 117-123.
[98] 
Kriaucionis S., Paterson A., Curtis J. et al.: Gene expression analysis exposes mitochondrial abnormalities in a mouse model of Rett syndrome. Mol Cell Biol 2006; 26: 5033-5042.
[99] 
Martinowich K., Hattori D., Wu H. et al.: DNA methylation-related chromatin remodeling in activity-dependent Bdnf gene regulation. Science 2003; 302: 890-893.
[100] 
Nomura T., Kimura M., Horii T. et al.: MeCP2-dependent repression of an imprinted miR-184 released by depolarization. Hum Mol Genet 2008; 17 (8): 1192-1199.
[101] 
Peddada S., Yasui D.H., LaSalle J.M.: Inhibitors of differentiation (ID1, ID2, ID3 and ID4) genes are neuronal targets of MeCP2 that are elevated in Rett syndrome. Hum Mol Genet 2006; 15: 2003-2014.
[102] 
Samaco R.C., Nagarajan R.P., Braunschweig D. et al.: Multiple pathways regulate MeCP2 expression in normal brain development and exhibit defects in autism-spectrum disorders. Hum Mol Genet 2004; 13(6): 629- 639.
[103] 
Li H., Radford J.C., Ragusa M.J. et al.: Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo. Proc Natl Acad Sci U S A 2008; 105 (27): 9397-9402.
Powrót
 

Najczęsciej pobierane
Semiologiczna i psychiatryczna charakterystyka dzieci z psychogennymi napadami rzekomopadaczkowymi
Neurol Dziec 2018; 27, 55: 11-14
Autyzm dziecięcy – współczesne spojrzenie
Neurol Dziec 2010; 19, 38: 75-78
Obraz bólów głowy w literaturze pięknej i poezji na podstawie wybranych utworów
Neurol Dziec 2016; 25, 50: 9-17

Narzędzia artykułu
Manager cytowań
Format:

Scholar Google
Artykuły aut.:Midro AT

PubMed
Artykuły aut.:Midro AT


Copyright © 2017 by Polskie Towarzystwo Neurologów Dziecięcych