Journal of Molecular Medicine

, Volume 81, Issue 6, pp 346–354 | Cite as

Rett syndrome: the complex nature of a monogenic disease

  • Alessandra Renieri
  • Ilaria Meloni
  • Ilaria Longo
  • Francesca Ariani
  • Francesca Mari
  • Chiara Pescucci
  • Franca Cambi
Invited Review


Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting almost exclusively girls. It is currently considered a monogenic X-linked dominant disorder due to mutations in MECP2 gene, encoding the methyl-CpG binding protein 2. A few RTT male cases, resulting from mosaicism for MECP2 mutations, have been reported. Male germline MECP2 mutations cause either severe encephalopathy with death at birth (usually in brothers of classical RTT females) or X-linked recessive mental retardation (XLMR). To date the wide phenotypic heterogeneity associated with MECP2 mutations in females (from classical RTT to healthy carriers) has been explained by differences in X chromosome inactivation. However, conflicting results have been obtained in different studies, with both random and highly skewed X-inactivation reported in healthy carrier females. Consequently it is possible that mechanisms other than X-inactivation play a role in the expressivity of MECP2 mutations. To explain the phenotypic heterogeneity associated with MECP2 mutations we propose a digenic model in which the presence of a "mutated" allele in a second gene, leading to a less functional protein, determines the clinical severity of the MECP2 mutation. The model is supported by the identification of the same mutation in XLMR and RTT cases. The carrier mothers of XLMR families are clinically asymptomatic and present balanced X chromosome inactivation. Therefore the same mutation arising in different genetic backgrounds can cause XLMR in males, remain silent in the carrier females and cause classic RTT in females. MECP2 mutations account for approximately 70–80% of classic RTT cases. MECP2 negative cases might result from mutations in noncoding regions of MECP2 gene. Alternatively, these cases might be due to mutations in other genes (locus heterogeneity). This hypothesis is supported by the identification of several chromosomal rearrangements in MECP2 negative patients with RTT and RTT-like phenotypes. MeCP2 is considered a general transcriptional repressor. However, conditional mouse mutants with selective loss of Mecp2 in the brain develop clinical manifestations similar to RTT, indicating that MECP2 is exclusively required for central nervous system function. The involvement of MeCP2 in methylation-specific transcriptional repression suggests that MECP2 related disorders result from dysregulated gene expression. Studies on gene expression have been performed in mouse and human brains. A relatively small number of gene expression changes were identified. It is possible that MeCP2 causes dysregulation of a very small subset of genes that are not detected with this method of analysis, or that very subtle changes in many genes cause the neuronal phenotype.


Rett syndrome Monogenic disorders Digenic disorders 



Methyl-CpG binding domain


Methyl-CpG binding protein


Methyl-CpG binding protein gene


Nonspecific X-linked mental retardation


Preserved speech variant


Rett syndrome


Transcription repression domain


X Chromosome inactivation


X-Linked mental retardation



This work was supported by Telethon grants GGP02372A and GTF02006 and by PAR 2001 and 2002 grants from the University of Siena to A.R.


  1. 1.
    Shahbazian M, Zoghbi H (2002) Rett syndrome and MeCP2: linking epigenetics and neuronal function. Am J Hum Genet 71:1259–1272CrossRefPubMedGoogle Scholar
  2. 2.
    Trevathan E, Moser HW (1988) Diagnostic criteria for Rett syndrome. Ann Neurol 23:425–428PubMedGoogle Scholar
  3. 3.
    Skjeldal OH, von Tetzchner S, Jacobsen K, Smith L (1995) Rett syndrome-distribution of phenotypes with special attention to the preserved speech variant. Neuropediatrics 26:87PubMedGoogle Scholar
  4. 4.
    Zappella M (1994) Rett syndrome-like hand washing, developmental arrest and autistic symptoms in two Italian girls. Eur Child Adolesc Psychiatry 3:52–56Google Scholar
  5. 5.
    Zappella M (1997) The preserved speech variant of the Rett complex: a report of 8 cases. Eur Child Adolesc Psychiatry 6:23–25PubMedGoogle Scholar
  6. 6.
    Zappella M, Gillberg C, Ehlers S (1998) The preserved speech variant: a subgroup of the Rett complex: a clinical report of 30 cases. J Autism Dev Disord 28:519–526PubMedGoogle Scholar
  7. 7.
    Zappella M (1992) The Rett girls with preserved speech. Brain Dev 14:98–101Google Scholar
  8. 8.
    Zappella M, Meloni I, Longo I, Canitano R, Hayek G, Rosaia L, Mari F, Renieri A (2003) Study of MECP2 gene in Rett syndrome variants and autistic girls. Am J Med Genet  10.1002/ajmg.b.10070
  9. 9.
    Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 23:185–188PubMedGoogle Scholar
  10. 10.
    Huppke P, Laccone F, Kramer N, Engel W, Hanefeld F (2000) Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients. Hum Mol Genet 9:1369–1375Google Scholar
  11. 11.
    Wan M, Lee SS, Zhang X, Houwink-Manville I, Song HR, Amir RE, Budden S, Naidu S, Pereira JL, Lo IF, Zoghbi HY, Schanen NC, Francke U (1999) Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots. Am J Hum Genet 65:1520–1529PubMedGoogle Scholar
  12. 12.
    Trappe R, Laccone F, Colibanschi J, Meins M, Huppke P, Hanefeld F, Engel W (2001) MECP2 mutations in sporadic cases of Rett syndrome are almost exclusively of paternal origin. Am J Hum Genet 68:1093–1101PubMedGoogle Scholar
  13. 13.
    Girard M, Couvert P, Carrié A, Tardieu M, Chelly J, Beldjord C, Bienvenu T (2001) Parental origin of de novo MECP2 mutations in Rett syndrome. Eur J Hum Genet 9:231–236CrossRefPubMedGoogle Scholar
  14. 14.
    Bienvenu T, Carrie A, de Roux N, Vinet MC, Jonveaux P, Couvert P, Villard L, Arzimanoglou A, Beldjord C, Fontes M, Tardieu M, Chelly J (2000) MECP2 mutations account for most cases of typical forms of Rett syndrome. Hum Mol Genet 9:1377–1384Google Scholar
  15. 15.
    Cheadle J, Gill H, Fleming N, Maynard J, Kerr A, Leonard H, Krawczak M, Cooper DN, Lynch S, Thomas N, Hughes H, Hulten M, Ravine D, Sampson JR, Clarke A (2000) Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location. Hum Mol Genet 9:1119–1129Google Scholar
  16. 16.
    De Bona C, Zappella M, Hayek G, Meloni I, Vitelli F, Bruttini M, Cusano R, Loffredo P, Longo I, Renieri A (2000) Preserved speech variant is allelic of classic Rett syndrome. Eur J Hum Genet 8:325–330PubMedGoogle Scholar
  17. 17.
    Laccone F, Huppke P, Hanefeld F, Meins M (2001) Mutation spectrum in patients with Rett syndrome in the German population: evidence of hot spot regions. Hum Mutat 17:183–190CrossRefPubMedGoogle Scholar
  18. 18.
    Nielsen JB, Henriksen KF, Hansen C, Silahtaroglu A, Schwartz M, Tommerup N (2001) MECP2 mutations in Danish patients with Rett syndrome: high frequency of mutations but no consistent correlations with clinical severity or with the X chromosome inactivation pattern. Eur J Hum Genet 9:178–184CrossRefPubMedGoogle Scholar
  19. 19.
    Zappella M, Meloni I, Longo I, Hayek G, Renieri A (2001) Preserved speech variants of the Rett syndrome: molecular and clinical analysis. Am J Med Genet 104:14–22PubMedGoogle Scholar
  20. 20.
    Clayton-Smith J, Watson P, Ramsden S, Black GC (2000) Somatic mutation in MECP2 as a non-fatal neurodevelopmental disorder in males. Lancet 356:830–832CrossRefPubMedGoogle Scholar
  21. 21.
    Topcu M, Akyerli C, Sayi A, Toruner A, Kocoglu SR, Cimbis M, Ozcelik T (2002) Somatic mosaicism for a MECP2 mutation associated with classic Rett syndrome in a boy. Eur J Hum Genet 10:77–81CrossRefPubMedGoogle Scholar
  22. 22.
    Villard L, Cardoso AK, Chelly PJ, Tardieu PM, Fontes M (2000) Two affected boys in a Rett syndrome family: clinical and molecular findings. Neurology 55:1188–1193PubMedGoogle Scholar
  23. 23.
    Meloni I, Bruttini M, Longo I, Mari F, Rizzolio F, D'Adamo P, Denvriendt K, Fryns J-P, Toniolo D, Renieri A (2000) A mutation in the Rett syndrome gene, MECP2, causes X-linked mental retardation and progressive spasticity in males. Am J Hum Genet 67:982–985Google Scholar
  24. 24.
    Couvert P, Bienvenu T, Aquaviva C, Poirier K, Moraine C, Gendrot C, Verloes A, Andres C, Le Fevre AC, Souville I, Steffann J, des Portes V, Ropers HH, Yntema HG, Fryns JP, Briault S, Chelly J, Cherif B (2001) MECP2 is highly mutated in X-linked mental retardation. Hum Mol Genet 10:941–946Google Scholar
  25. 25.
    Yntema H, Oudakker A, Kleefstra T, Hamel B, van Bokhoven H, Chelly J, Kalscheuer V, Fryns J, Raynaud M, Moizard M, Moraine C (2002) In-frame deletion in MECP2 causes mild nonspecific mental retardation. Am J Med Genet 107:81–83PubMedGoogle Scholar
  26. 26.
    Winnepenninckx B, Errijgers V, Hayez-Delatte F, Reyniers E, Frank Kooy R (2002) Identification of a family with nonspecific mental retardation (MRX79) with the A140 V mutation in the MECP2 gene: is there a need for routine screening? Hum Mutat 20:249–252Google Scholar
  27. 27.
    D'Esposito M, Quaderi NA, Ciccodicola A, Bruni P, Esposito T, D'Urso M, Brown SDM (1996) Isolation, physical mapping, and Northern analysis of the X-linked human gene encoding methyl CpG-binding protein, MECP2. Mammal Genome 7:533–535Google Scholar
  28. 28.
    Jones PL, Veenstra GJ, Wade PA, Vermaak D, Kass SU, Landsberger N, Strouboulis J, Wolffe AP (1998) Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet 19:187–191PubMedGoogle Scholar
  29. 29.
    Kokura K, Kaul S, Wadhwa R, Nomura T, Khan M, Shinagawa T, Yasukawa T, Colmenares C, Ishii S (2001) The Ski protein family is required for MeCP2-mediated transcriptional repression. J Biol Chem 276:34115–34121CrossRefPubMedGoogle Scholar
  30. 30.
    Kaludov NK, Wolffe AP (2000) MeCP2 driven transcriptional repression in vito: selectivity for methylated DNA, action at a distance and contacts with the basal transcription machinery. Nucleic Acids Res 28:1921–1928PubMedGoogle Scholar
  31. 31.
    Yusufzai TM, Wolffe AP (2000) Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res 28:4172–4179CrossRefPubMedGoogle Scholar
  32. 32.
    Colvin L, Fyfe S, Leonard S, Schiavello T, Ellaway C, De Klerk N, Christodoulou J, Msall M, Leonard H (2003) Describing the phenotype in Rett syndrome using a population database. Arch Dis Child 88:38–43CrossRefPubMedGoogle Scholar
  33. 33.
    Amir RE, Van den Veyver IB, Schultz R, Malicki DM, Tran CQ, Dahle EJ, Philippi A, Timar L, Percy AK, Motil KJ, Lichtarge O, Smith EO, Glaze DG, Zoghbi HY (2000) Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes. Ann Neurol 47:670–679PubMedGoogle Scholar
  34. 34.
    Monros E, Armstrong J, Aibar E, Poo P, Canos I, Pineda M (2001) Rett syndrome in Spain: mutation analysis and clinical correlations. Brain Dev [Suppl 1]:S251–S253Google Scholar
  35. 35.
    Huppke P, Held M, Hanefeld F, Engel W, Laccone F (2002) Influence of mutation type and location on phenotype in 123 patients with Rett syndrome. Neuropediatrics 33:105–108CrossRefPubMedGoogle Scholar
  36. 36.
    Imessaoudene B, Bonnefont J, Royer G, Cormier-Daire V, Lyonnet S, Lyon G, Munnich A, Amiel J (2001) MECP2 mutation in non-fatal, non-progressive encephalopathy in a male. J Med Genet 38:171–174CrossRefPubMedGoogle Scholar
  37. 37.
    Orrico A, Lam, C-W, Galli L, Dotti MT, Hayek G, Tong SF, Poon, PMK, Zappella M, Federico A, Sorrentino V (2000) MECP2 mutation in male with non-specific X-linked mental retardation. FEBS Lett 24106:1–4Google Scholar
  38. 38.
    Cohen D, Lazar G, Couvert P, Desportes V, Lippe D, Mazet P, Heron D (2002) MECP2 mutation in a boy with language disorder and schizophrenia. Am J Psychiatry 159:149–149CrossRefPubMedGoogle Scholar
  39. 39.
    Moncla A, Kpebe A, Missirian C, Mancini J, Villard L (2002) Polymorphisms in the C-terminal domain of MECP2 in mentally handicapped boys: implications for genetic counseling. Eur J Hum Genet 10:86–89PubMedGoogle Scholar
  40. 40.
    Yntema HG, Kleefstra T, Oudakker AR, de Vries, et al. (2002) Low frequency of MECP2 mutations in mental retardation of unknown origin: implications for routine DNA diagnostics. Nature, StrasbourgGoogle Scholar
  41. 41.
    Laccone F, Zoll B, Huppke P, Hanefeld F, Pepinski W, Trappe R (2002) MECP2 gene nucleotide changes and their pathogenicity in males: proceed with caution. J Med Genet 39:586–588CrossRefPubMedGoogle Scholar
  42. 42.
    Ishii T, Makita Y, Ogawa A, Amamiya S, Yamamoto M, Miyamoto A, Oki J (2001) The role of different X-inactivation pattern on the variable clinical phenotype with Rett syndrome. Brain Dev [Suppl 1]:S161–S164Google Scholar
  43. 43.
    Sharp A, Robinson D, Jacobs P (2000) Age- and tissue-specific variation of X chromosome inactivation ratios in normal women. Hum Genet 107:343–349PubMedGoogle Scholar
  44. 44.
    Zoghbi HY, Percy AK, Schultz RJ, Fill C (1990) Patterns of X chromosome inactivation in the Rett syndrome. Brain Dev 12:131–135PubMedGoogle Scholar
  45. 45.
    Shahbazian MD, Sun Y, Zoghbi HY (2002) Balanced X chromosome inactivation patterns in the Rett syndrome brain. Am J Med Genet 111:164–168CrossRefPubMedGoogle Scholar
  46. 46.
    LaSalle JM, Goldstine J, Balmer D, Greco CM (2001) Quantitative localization of heterogeneous methyl-CpG-binding protein 2 (MeCP2) expression phenotypes in normal and Rett syndrome brain by laser scanning cytometry. Hum Mol Genet 10:1729–1740PubMedGoogle Scholar
  47. 47.
    Yntema H, Kleefstra T, Oudakker A, de Vries B, Nillesen W, Sistermans E, Brunner H, Hamel B, van Bokhoven H (2002) Low frequency of MECP2 mutations in mental retardation of unknown origin: implications for routine DNA diagnostics. Nature, StrasbourgGoogle Scholar
  48. 48.
    Sirianni N, Naidu S, Pereira J, Pillotto R, Hoffman E (1998) Rett syndrome: confirmation of X-linked dominant inheritance, and localization of the gene to Xq28. Am J Hum Genet 63:1552–1558PubMedGoogle Scholar
  49. 49.
    Schollen E, Deflem E, Smeets E, Fryns J, Matthijs G (2002) Gross rearrangements in the MECP2 gene in two patients with Rett syndrome. University of Chicago Press, BaltimoreGoogle Scholar
  50. 50.
    Villard L, Levy N, Xiang F, Kpebe A, Labelle V, Chevillard C, Zhang Z, Schwartz C, Tardieu M, Chelly J, Anvret M, Fontes M (2001) 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 38:435–442CrossRefPubMedGoogle Scholar
  51. 51.
    Delobel B, Delannoy V, Pini G, Zapella M, Tardieu M, Vallée L, Croquette MF (1998) Identification and molecular characterization of a small 11q23.3 de novo duplication in a patient with Rett syndrome manifestations. Am J Med Genet 80:273–280CrossRefPubMedGoogle Scholar
  52. 52.
    Gordon K, Siu Mok V, Sergovich F, Jung J (1993) 18q-mosaicism associated with Rett syndrome phenotype. Am J Med Genet 46:142–144PubMedGoogle Scholar
  53. 53.
    Gustavsson P, Kimber E, Wahlstrom J, Annerén G (1999) Monosomy 18q syndrome and atypical Rett syndrome in a girl with an interstitial deletion (18)(q21.1q22.3). Am J Med Genet 82:348–351Google Scholar
  54. 54.
    Wahlstrom J, Uller A, Johannesson T, Holmqvist D, Darnfors C, Vujic M, Tonnby B, Hagberg B, Martinsson T (1999) Congenital variant Rett syndrome in a girl with terminal deletion of chromosome 3p. J Med Genet 36:343–345PubMedGoogle Scholar
  55. 55.
    Simonic I, Gericke GS, Lippert M, Schoeman JF (1997) Additional clinical and cytogenetic findings associated with Rett syndrome. Am J Med Genet 74:331–337PubMedGoogle Scholar
  56. 56.
    Journel H, Melki J, Turleau C, Munnich A, de Grouchy J (1990) Rett phenotype with X/autosome translocation: possible mapping to the short arm of chromosome X. Am J Med Genet 35:142–147PubMedGoogle Scholar
  57. 57.
    Zoghbi HY, Ledbetter D, Schultz R, Percy A, Glaze D (1990) A de novo X;3 translocation in Rett syndrome. Am J Med Genet 35:148–151PubMedGoogle Scholar
  58. 58.
    Balmer D, Goldstine J, Rao YM, LaSalle JM (2003) Elevated methyl-CpG-binding protein 2 expression is acquired during postnatal human brain development and is correlated with alternative polyadenylation. J Mol Med 81:61–68PubMedGoogle Scholar
  59. 59.
    Chen RZ, Akbarian S, Tudor M, Jaenisch R (2001) Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nat Genet 27:327–331Google Scholar
  60. 60.
    Guy J, Hendrich B, Holmes M, Martin JE, Bird A (2001) A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat Genet 27:322–326Google Scholar
  61. 61.
    Shahbazian M, Young J, Yuva-Paylor L, Spencer C, Antalffy B, Noebels J, Armstrong D, Paylor R, Zoghbi H (2002) Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3. Neuron 35:234–254Google Scholar
  62. 62.
    Ng H, Zhang Y, Hendrich B, Johnson C, Turner B, Erdjument-Bromage H, Tempst P, Reinberg D, Bird A (1999) MBD2 is a transcriptional repressor belonging to MeCP1 histone deacetylase complex. Nat Genet 23:58–61PubMedGoogle Scholar
  63. 63.
    Colantuoni C, Jeon E, Hyder K, Chenchik A, Khimani AH, Narayanan V, Hoffman EP, Kaufmann WE, Naidu S, Pevsner J (2001) Gene expression profiling in postmortem Rett syndrome brain: differential gene expression and patient classification. Neurobiol Dis 8:847–865CrossRefPubMedGoogle Scholar
  64. 64.
    Deguchi K, Antalffy BA, Twohill LJ, Chakraborty S, Glaze DG, Armstrong DD (2000) Substance P immunoreactivity in Rett syndrome. Pediatr Neurol 22:259–266CrossRefPubMedGoogle Scholar
  65. 65.
    Johnston M, Jeon O, Pevsner J, Blue M, Naidu S (2001) Neurobiology of Rett syndrome: a genetic disorder of synapse development. Brain Dev [Suppl 1]:S206–S213Google Scholar
  66. 66.
    Armstrong D, et al (1995) Selective dendritic alterations in the cortex of Rett syndrome. Neuropathol Exp Neurol 54:195–201Google Scholar
  67. 67.
    Tudor M, Akbarian S, Chen R, Jaenisch R (2002) Transcriptional profiling of a mouse model for Rett syndrome reveals subtle transcriptional changes in the brain. Proc Natl Acad Sci USA 99:15536–15541CrossRefGoogle Scholar
  68. 68.
    Traynor J, Agarwal JP, Lazzeroni L, Francke U (2002) Gene expression patterns vary in clonal cell cultures from Rett syndrome females with eight different MECP2 mutations. BMC Med Genet 3:12CrossRefPubMedGoogle Scholar
  69. 69.
    Balmer D, Arredondo J, Samaco RC, LaSalle JM (2002) MECP2 mutations in Rett syndrome adversely affect lymphocyte growth, but do not affect imprinted gene expression in blood or brain. Hum Genet 110:545–552CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Alessandra Renieri
    • 1
  • Ilaria Meloni
    • 1
  • Ilaria Longo
    • 1
  • Francesca Ariani
    • 1
  • Francesca Mari
    • 1
  • Chiara Pescucci
    • 1
  • Franca Cambi
    • 2
  1. 1.Medical Genetics, Policlinico Le ScotteUniversity of SienaSienaItaly
  2. 2.Department of Neurology, Jefferson Medical CollegeThomas Jefferson UniversityPhiladelphiaUSA

Personalised recommendations