MECP2 disorders: from the clinic to mice and back
Laura Marie Lombardi, … , Steven Andrew Baker, Huda Yahya Zoghbi
Laura Marie Lombardi, … , Steven Andrew Baker, Huda Yahya Zoghbi
Published August 3, 2015
Citation Information: J Clin Invest. 2015;125(8):2914-2923. https://doi.org/10.1172/JCI78167.
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Review

MECP2 disorders: from the clinic to mice and back

Abstract

Two severe, progressive neurological disorders characterized by intellectual disability, autism, and developmental regression, Rett syndrome and MECP2 duplication syndrome, result from loss and gain of function, respectively, of the same critical gene, methyl-CpG–binding protein 2 (MECP2). Neurons acutely require the appropriate dose of MECP2 to function properly but do not die in its absence or overexpression. Instead, neuronal dysfunction can be reversed in a Rett syndrome mouse model if MeCP2 function is restored. Thus, MECP2 disorders provide a unique window into the delicate balance of neuronal health, the power of mouse models, and the importance of chromatin regulation in mature neurons. In this Review, we will discuss the clinical profiles of MECP2 disorders, the knowledge acquired from mouse models of the syndromes, and how that knowledge is informing current and future clinical studies.

Authors

Laura Marie Lombardi, Steven Andrew Baker, Huda Yahya Zoghbi

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Figure 1

MeCP2 protein structure and Rett syndrome–causing mutations.

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MeCP2 protein structure and Rett syndrome–causing mutations. (A) Human M...
(A) Human MeCP2 is expressed from either of two alternatively spliced transcripts that differ only in their inclusion of exon 2. Structures are traditionally referred to by their location within the sequence of MeCP2-e2, the slightly shorter protein isoform produced from translation initiating at exon 2, as shown (486 amino acids). The MBD was identified by deletion mapping to residues 78–162. The ability of MeCP2 to repress methylated reporters in vitro is dependent on amino acids 207–310 (TRD). The region between these domains is frequently referred to as the ID. (B) Conserved domains within MeCP2 are indicated on the basis of an alignment of human, mouse, rat, frog, and fish MECP2 orthologs. A large stretch of highly conserved amino acids overlaps with the MBD (amino acids 72–166). The two highly conserved AT-hooks are indicated, and a highly conserved stretch of histidines is located in the C-terminus. (C) Over 80 unique missense and 140 unique truncating mutations have been identified in girls with Rett syndrome. Recurrent, Rett-causing mutations are indicated along the MeCP2 protein sequence (150). Missense mutations are indicated above and are found within highly conserved motifs within the MeCP2 sequence. Truncating mutations are indicated below. Less common truncating mutations are not shown. Truncating mutations located before and including R270X are associated with more severe symptoms when compared with those of R294X or more C-terminal–truncating mutations, as indicated at the bottom of the diagram.