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.

Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts

“…This 100-kb de novo Xq28 deletion encompassed all or part of the TMEM187, MIR3202-1, MIR3202-2, IRAK1, MIR718, and MECP2 genes. The absence of the MECP2 gene was consistent with the patient's clinical phenotype, as congenital encephalopathy, hypotonia, and respiratory insufficiency are commonly reported in boys with neonatal encephalopathy due to MECP2 deficiency (78)(79)(80)(81)(82)(83)(84)(85)(86)(87)(88)(89)(90)(91). The lack of TMEM187, MIR3202-1, MIR3202-2, and MIR718 was not associated with any overt phenotype at the time of the patient's death at the age of 7 mo.…”

“…Rett syndrome is characterized principally by arrested development at about 12 mo of age, the regression of acquired skills, a reduction or total loss of communication, and stereotypic hand movements (77). Boys carrying LOF mutations of MECP2 present with various neurological phenotypes, from Rett-like syndrome (very rare) to severe neonatal encephalopathy commonly accompanied by respiratory insufficiency, hypotonia, and early childhood death (78)(79)(80)(81)(82)(83)(84)(85)(86)(87)(88)(89)(90)(91). MECP2 duplication syndrome is a severe neurodevelopmental disorder (fully penetrant in boys) characterized by hypotonia, severe intellectual disability, speech abnormalities, seizures, and recurrent life-threatening infections (92).…”

5-hydroxymethylcytosine accumulation in postmitotic neurons results in functional demethylation of expressed genes

“…2C). Thus, highly expressed genes bind low levels of MeCP2 and poorly expressed genes are enriched in MeCP2 binding, in agreement with a repressive role for MeCP2 in transcription (17,18,29). To reveal the relative contribution of each type of modified cytosine to MeCP2 binding in expressed genes we applied the random forest regressor algorithm (30).…”

“…Thus, MeCP2 binds with similar high affinities to 5mCG, 5mCA, and 5hmCA containing DNA, but its binding to 5hmCG occurs at a low affinity similar to that measured for unmethylated DNA. Given the importance of MeCP2 for normal neuronal function demonstrated through studies of Rett syndrome mouse models (17,18) and the differences in MeCP2 binding to 5hmCG and 5hmCA containing DNA (14-16), we have employed 5hmC mapping using bisulfitesequencing data (MethylC-Seq) (10) and oxidative bisulfite sequencing (oxBS-Seq) (19), high-resolution mapping of native MeCP2 binding sites using the Occupied Regions of Genomes from Affinity-purified Naturally Isolated Chromatin (ORGANIC) approach (20), and ChIP mapping of informative histone modifications to understand the biochemical consequences of 5hmC accumulation in a single neuronal cell type in vivo.…”

Human neural crest cells contribute to coat pigmentation in interspecies chimeras after in utero injection into mouse embryos

“…human neural crest cells | chimera | embryonic stem cells | melanocytes G enetically engineered mice have been highly informative in studying the developmental origin of many inherited diseases (1)(2)(3). However, mouse models often fail to reproduce the pathophysiology of human disorders due to interspecies divergence, such as metabolic differences between mouse and human (4), or differences in genetic background (5).…”