3c2i

Structural highlights

Disease

[MECP2_HUMAN] Defects in MECP2 may be a cause of Angelman syndrome (AS) [MIM:105830]; also known as happy puppet syndrome. AS is a neurodevelopmental disorder characterized by severe mental retardation, absent speech, ataxia, sociable affect and dysmorphic facial features. AS and Rett syndrome have overlapping clinical features.^{[1] [2]} Defects in MECP2 are the cause of mental retardation syndromic X-linked type 13 (MRXS13) [MIM:300055]. Mental retardation is a mental disorder characterized by significantly sub-average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period. MRXS13 patients manifest mental retardation associated with other variable features such as spasticity, episodes of manic depressive psychosis, increased tone and macroorchidism.^{[3] [4] [5] [6] [7] [8] [9] [10] [11]} Defects in MECP2 are the cause of Rett syndrome (RTT) [MIM:312750]. RTT is an X-linked dominant disease, it is a progressive neurologic developmental disorder and one of the most common causes of mental retardation in females. Patients appear to develop normally until 6 to 18 months of age, then gradually lose speech and purposeful hand movements and develop microcephaly, seizures, autism, ataxia, intermittent hyperventilation, and stereotypic hand movements. After initial regression, the condition stabilizes and patients usually survive into adulthood.^{[12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33]} Defects in MECP2 may be the cause of susceptibility autism X-linked type 3 (AUTSX3) [MIM:300496]. AUTSX3 is a pervasive developmental disorder (PDD), prototypically characterized by impairments in reciprocal social interaction and communication, restricted and stereotyped patterns of interests and activities, and the presence of developmental abnormalities by 3 years of age.^[34] Defects in MECP2 are the cause of encephalopathy neonatal severe due to MECP2 mutations (ENS-MECP2) [MIM:300673]. Note=The MECP2 gene is mutated in Rett syndrome, a severe neurodevelopmental disorder that almost always occurs in females. Although it was first thought that MECP2 mutations causing Rett syndrome were lethal in males, later reports identified a severe neonatal encephalopathy in surviving male sibs of patients with Rett syndrome. Additional reports have confirmed a severe phenotype in males with Rett syndrome-associated MECP2 mutations.^[35] Defects in MECP2 are the cause of mental retardation syndromic X-linked Lubs type (MRXSL) [MIM:300260]. Mental retardation is characterized by significantly below average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period. MRXSL patients manifest mental retardation associated with variable features. They include swallowing dysfunction and gastroesophageal reflux with secondary recurrent respiratory infections, hypotonia, mild myopathy and characteristic facies such as downslanting palpebral fissures, hypertelorism and a short nose with a low nasal bridge. Note=Increased dosage of MECP2 due to gene duplication appears to be responsible for the mental retardation phenotype.

Function

[MECP2_HUMAN] Chromosomal protein that binds to methylated DNA. It can bind specifically to a single methyl-CpG pair. It is not influenced by sequences flanking the methyl-CpGs. Mediates transcriptional repression through interaction with histone deacetylase and the corepressor SIN3A.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

• Introduction to Evolutionary Conservation
• Methyl CpG Binding Protein 2
• Methyl CpG binding protein

References

1. ↑ Inui K, Akagi M, Ono J, Tsukamoto H, Shimono K, Mano T, Imai K, Yamada M, Muramatsu T, Sakai N, Okada S. Mutational analysis of MECP2 in Japanese patients with atypical Rett syndrome. Brain Dev. 2001 Jul;23(4):212-5. PMID:11376998
2. ↑ Watson P, Black G, Ramsden S, Barrow M, Super M, Kerr B, Clayton-Smith J. Angelman syndrome phenotype associated with mutations in MECP2, a gene encoding a methyl CpG binding protein. J Med Genet. 2001 Apr;38(4):224-8. PMID:11283202
3. ↑ Meloni I, Bruttini M, Longo I, Mari F, Rizzolio F, D'Adamo P, Denvriendt K, Fryns JP, Toniolo D, Renieri A. A mutation in the rett syndrome gene, MECP2, causes X-linked mental retardation and progressive spasticity in males. Am J Hum Genet. 2000 Oct;67(4):982-5. Epub 2000 Sep 12. PMID:10986043 doi:10.1086/303078
4. ↑ Orrico A, Lam C, Galli L, Dotti MT, Hayek G, Tong SF, Poon PM, Zappella M, Federico A, Sorrentino V. MECP2 mutation in male patients with non-specific X-linked mental retardation. FEBS Lett. 2000 Sep 22;481(3):285-8. PMID:11007980
5. ↑ 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. MECP2 is highly mutated in X-linked mental retardation. Hum Mol Genet. 2001 Apr 15;10(9):941-6. PMID:11309367
6. ↑ Klauck SM, Lindsay S, Beyer KS, Splitt M, Burn J, Poustka A. A mutation hot spot for nonspecific X-linked mental retardation in the MECP2 gene causes the PPM-X syndrome. Am J Hum Genet. 2002 Apr;70(4):1034-7. Epub 2002 Feb 15. PMID:11885030 doi:10.1086/339553
7. ↑ Winnepenninckx B, Errijgers V, Hayez-Delatte F, Reyniers E, Frank Kooy R. Identification of a family with nonspecific mental retardation (MRX79) with the A140V mutation in the MECP2 gene: is there a need for routine screening? Hum Mutat. 2002 Oct;20(4):249-52. PMID:12325019 doi:10.1002/humu.10130
8. ↑ Laccone F, Zoll B, Huppke P, Hanefeld F, Pepinski W, Trappe R. MECP2 gene nucleotide changes and their pathogenicity in males: proceed with caution. J Med Genet. 2002 Aug;39(8):586-8. PMID:12161600
9. ↑ Dotti MT, Orrico A, De Stefano N, Battisti C, Sicurelli F, Severi S, Lam CW, Galli L, Sorrentino V, Federico A. A Rett syndrome MECP2 mutation that causes mental retardation in men. Neurology. 2002 Jan 22;58(2):226-30. PMID:11805248
10. ↑ Moog U, Smeets EE, van Roozendaal KE, Schoenmakers S, Herbergs J, Schoonbrood-Lenssen AM, Schrander-Stumpel CT. Neurodevelopmental disorders in males related to the gene causing Rett syndrome in females (MECP2). Eur J Paediatr Neurol. 2003;7(1):5-12. PMID:12615169
11. ↑ Ventura P, Galluzzi R, Bacca SM, Giorda R, Massagli A. A novel familial MECP2 mutation in a young boy: clinical and molecular findings. Neurology. 2006 Sep 12;67(5):867-8. PMID:16966553 doi:10.1212/01.wnl.0000233990.87889.15
12. ↑ Inui K, Akagi M, Ono J, Tsukamoto H, Shimono K, Mano T, Imai K, Yamada M, Muramatsu T, Sakai N, Okada S. Mutational analysis of MECP2 in Japanese patients with atypical Rett syndrome. Brain Dev. 2001 Jul;23(4):212-5. PMID:11376998
13. ↑ Watson P, Black G, Ramsden S, Barrow M, Super M, Kerr B, Clayton-Smith J. Angelman syndrome phenotype associated with mutations in MECP2, a gene encoding a methyl CpG binding protein. J Med Genet. 2001 Apr;38(4):224-8. PMID:11283202
14. ↑ Laccone F, Zoll B, Huppke P, Hanefeld F, Pepinski W, Trappe R. MECP2 gene nucleotide changes and their pathogenicity in males: proceed with caution. J Med Genet. 2002 Aug;39(8):586-8. PMID:12161600
15. ↑ Mnatzakanian GN, Lohi H, Munteanu I, Alfred SE, Yamada T, MacLeod PJ, Jones JR, Scherer SW, Schanen NC, Friez MJ, Vincent JB, Minassian BA. A previously unidentified MECP2 open reading frame defines a new protein isoform relevant to Rett syndrome. Nat Genet. 2004 Apr;36(4):339-41. Epub 2004 Mar 21. PMID:15034579 doi:10.1038/ng1327
16. ↑ 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. Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots. Am J Hum Genet. 1999 Dec;65(6):1520-9. PMID:10577905 doi:10.1086/302690
17. ↑ Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999 Oct;23(2):185-8. PMID:10508514 doi:10.1038/13810
18. ↑ Buyse IM, Fang P, Hoon KT, Amir RE, Zoghbi HY, Roa BB. Diagnostic testing for Rett syndrome by DHPLC and direct sequencing analysis of the MECP2 gene: identification of several novel mutations and polymorphisms. Am J Hum Genet. 2000 Dec;67(6):1428-36. Epub 2000 Oct 30. PMID:11055898 doi:10.1086/316913
19. ↑ Cheadle JP, 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. Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location. Hum Mol Genet. 2000 Apr 12;9(7):1119-29. PMID:10767337
20. ↑ 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. MECP2 mutations account for most cases of typical forms of Rett syndrome. Hum Mol Genet. 2000 May 22;9(9):1377-84. PMID:10814719
21. ↑ Amano K, Nomura Y, Segawa M, Yamakawa K. Mutational analysis of the MECP2 gene in Japanese patients with Rett syndrome. J Hum Genet. 2000;45(4):231-6. PMID:10944854 doi:10.1007/s100380070032
22. ↑ Xiang F, Buervenich S, Nicolao P, Bailey ME, Zhang Z, Anvret M. Mutation screening in Rett syndrome patients. J Med Genet. 2000 Apr;37(4):250-5. PMID:10745042
23. ↑ Obata K, Matsuishi T, Yamashita Y, Fukuda T, Kuwajima K, Horiuchi I, Nagamitsu S, Iwanaga R, Kimura A, Omori I, Endo S, Mori K, Kondo I. Mutation analysis of the methyl-CpG binding protein 2 gene (MECP2) in patients with Rett syndrome. J Med Genet. 2000 Aug;37(8):608-10. PMID:10991688
24. ↑ Hampson K, Woods CG, Latif F, Webb T. Mutations in the MECP2 gene in a cohort of girls with Rett syndrome. J Med Genet. 2000 Aug;37(8):610-2. PMID:10991689
25. ↑ Armstrong J, Pineda M, Aibar E, Gean E, Monros E. Classic Rett syndrome in a boy as a result of somatic mosaicism for a MECP2 mutation. Ann Neurol. 2001 Nov;50(5):692. PMID:11706982
26. ↑ Giunti L, Pelagatti S, Lazzerini V, Guarducci S, Lapi E, Coviello S, Cecconi A, Ombroni L, Andreucci E, Sani I, Brusaferri A, Lasagni A, Ricotti G, Giometto B, Nicolao P, Gasparini P, Granatiero M, Uzielli ML. Spectrum and distribution of MECP2 mutations in 64 Italian Rett syndrome girls: tentative genotype/phenotype correlation. Brain Dev. 2001 Dec;23 Suppl 1:S242-5. PMID:11738883
27. ↑ Laccone F, Huppke P, Hanefeld F, Meins M. Mutation spectrum in patients with Rett syndrome in the German population: Evidence of hot spot regions. Hum Mutat. 2001 Mar;17(3):183-90. PMID:11241840 doi:10.1002/humu.3
28. ↑ Vacca M, Filippini F, Budillon A, Rossi V, Mercadante G, Manzati E, Gualandi F, Bigoni S, Trabanelli C, Pini G, Calzolari E, Ferlini A, Meloni I, Hayek G, Zappella M, Renieri A, D'Urso M, D'Esposito M, MacDonald F, Kerr A, Dhanjal S, Hulten M. Mutation analysis of the MECP2 gene in British and Italian Rett syndrome females. J Mol Med (Berl). 2001;78(11):648-55. PMID:11269512
29. ↑ Hoffbuhr K, Devaney JM, LaFleur B, Sirianni N, Scacheri C, Giron J, Schuette J, Innis J, Marino M, Philippart M, Narayanan V, Umansky R, Kronn D, Hoffman EP, Naidu S. MeCP2 mutations in children with and without the phenotype of Rett syndrome. Neurology. 2001 Jun 12;56(11):1486-95. PMID:11402105
30. ↑ Conforti FL, Mazzei R, Magariello A, Patitucci A, Gabriele AL, Muglia M, Quattrone A, Fiumara A, Barone R, Pavone L, Nistico R, Mangone L. Mutation analysis of the MECP2 gene in patients with Rett syndrome. Am J Med Genet A. 2003 Mar 1;117A(2):184-7. PMID:12567420 doi:10.1002/ajmg.a.10898
31. ↑ Hammer S, Dorrani N, Hartiala J, Stein S, Schanen NC. Rett syndrome in a 47,XXX patient with a de novo MECP2 mutation. Am J Med Genet A. 2003 Oct 15;122A(3):223-6. PMID:12966522 doi:http://dx.doi.org/10.1002/ajmg.a.20320
32. ↑ Smeets E, Schollen E, Moog U, Matthijs G, Herbergs J, Smeets H, Curfs L, Schrander-Stumpel C, Fryns JP. Rett syndrome in adolescent and adult females: clinical and molecular genetic findings. Am J Med Genet A. 2003 Oct 15;122A(3):227-33. PMID:12966523 doi:http://dx.doi.org/10.1002/ajmg.a.20321
33. ↑ Schanen C, Houwink EJ, Dorrani N, Lane J, Everett R, Feng A, Cantor RM, Percy A. Phenotypic manifestations of MECP2 mutations in classical and atypical Rett syndrome. Am J Med Genet A. 2004 Apr 15;126A(2):129-40. PMID:15057977 doi:10.1002/ajmg.a.20571
34. ↑ Carney RM, Wolpert CM, Ravan SA, Shahbazian M, Ashley-Koch A, Cuccaro ML, Vance JM, Pericak-Vance MA. Identification of MeCP2 mutations in a series of females with autistic disorder. Pediatr Neurol. 2003 Mar;28(3):205-11. PMID:12770674
35. ↑ Imessaoudene B, Bonnefont JP, Royer G, Cormier-Daire V, Lyonnet S, Lyon G, Munnich A, Amiel J. MECP2 mutation in non-fatal, non-progressive encephalopathy in a male. J Med Genet. 2001 Mar;38(3):171-4. PMID:11238684
36. ↑ Ho KL, McNae IW, Schmiedeberg L, Klose RJ, Bird AP, Walkinshaw MD. MeCP2 binding to DNA depends upon hydration at methyl-CpG. Mol Cell. 2008 Feb 29;29(4):525-31. PMID:18313390 doi:10.1016/j.molcel.2007.12.028