MECP2 mutants R106W, D121G, R133H, S134F, T158M and T158A do not bind to 5mC-DNA

Stable Identifier
Reaction [transition]
Homo sapiens
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MECP2 T158M mutation is the most frequent missense mutation in Rett syndrome. MECP2 T158A mutation also causes Rett syndrome but is rarely reported. Threonine 158 (T158) of MECP2 plays a structurally important role in forming the tandem Asx-ST motif in the methyl-CpG-binding domain (MBD) of MECP2, which is critical for DNA binding. MECP2 T158M and other MECP2 T158 mutants are unable to efficiently bind 5mC-DNA (DNA containing 5-methylcytosine mark, associated with repressed transcription) (Ho et al. 2008, Goffin et al. 2012). In addition, MECP2 T158M and MECP2 T158A mutants show decreased protein stability, which further contributes to their loss of function (Goffin et al. 2012). MECP2 R106W is the second most frequently reported Rett syndrome mutation. Arginine 106 (R106) of MECP2 is part of the DNA-binding Asx-ST motif in the MBD of MECP2 (Ho et al. 2008) and MECP2 R106W mutant is unable to interact with the 5mC-DNA (Ghosh et al. 2008). MECP2 mutant proteins D121G, R133H and S134F lose the ability to bind to 5mC-DNA. These mutants also lose the ability to bind to 5hmC-DNA (DNA containing 5-hydroxymethylcytosine mark, associated with active transcription) (Mellen et al. 2012).

Literature References
PubMed ID Title Journal Year
18313390 MeCP2 binding to DNA depends upon hydration at methyl-CpG

Schmiedeberg, L, Ho, KL, Bird, AP, McNae, IW, Klose, RJ, Walkinshaw, MD

Mol. Cell 2008
23260135 MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system

Dewell, S, Heintz, N, Mellén, M, Kriaucionis, S, Ayata, P

Cell 2012
22119903 Rett syndrome mutation MeCP2 T158A disrupts DNA binding, protein stability and ERP responses

Greenberg, ME, Siegel, SJ, Blendy, JA, Carlson, GC, Goffin, D, Ong, C, Hu, L, Cohen, S, Wang, IT, Zhang, L, Mercado-Berton, A, Amorim, M, Reyes, AR, Zhou, Z, Allen, M

Nat. Neurosci. 2011
18499664 Rett syndrome-causing mutations in human MeCP2 result in diverse structural changes that impact folding and DNA interactions

Horowitz-Scherer, RA, Gierasch, LM, Ghosh, RP, Nikitina, T, Woodcock, CL

J. Biol. Chem. 2008
Normal reaction
Functional status

Loss of function of MECP2 R106W, MECP2 D121G,MECP2 R133H,MECP2S134F,MECP2 T158M/A [nucleoplasm]

Name Identifier Synonyms
Rett syndrome DOID:1206 Rett's disorder, cerebroatrophic hyperammonemia
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