The involvement of epigenetic defects in mental retardation

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Abstract

Mental retardation is a group of cognitive disorders with a significant worldwide prevalence rate. This high rate, together with the considerable familial and societal burden resulting from these disorders, makes it an important focus for prevention and intervention. While the diseases associated with mental retardation are diverse, a significant number are linked with disruptions in epigenetic mechanisms, mainly due to loss-of-function mutations in genes that are key components of the epigenetic machinery. Additionally, several disorders classed as imprinting syndromes are associated with mental retardation. This review will discuss the epigenetic abnormalities associated with mental retardation, and will highlight their importance for diagnosis, treatment, and prevention of these disorders.

Highlights

► A number of diseases characterized by mental retardation are associated with disruptions in epigenetic mechanisms. ► Mutations in genes encoding key components of the epigenetic machinery, and imprinting syndromes have been linked to intellectual impairments. ► Research into the role of epigenetic abnormalities in mental retardation is an important focus for its diagnosis, treatment and prevention.

Introduction

The occurrence rate of many diseases with a suspected genetic basis often does not match predictions from traditional genetics. One of the most striking examples of such discordance is the disease risk of monozygotic twins who, despite having an identical genetic make-up, have notably different susceptibility to diseases (Haque, Gottesman, & Wong, 2009). Although still not well understood or explained, it is now largely recognized that further to the genome, the epigenome is of crucial importance for such differences, and influences an individual’s disease risk. The epigenome is different in each individual, and significantly fluctuates across life. It is strongly influenced by the environment, and varies between each individual, including between monozygotic twins, depending on such factors as lifestyle, diet, living conditions, and age (Fraga et al., 2005). The epigenome therefore plays an extremely important role in many diseases ranging from cancer to neurodevelopmental and neurodegenerative disorders. Here we review the current evidence that anomalies in epigenetic marks, and in the components of the epigenetic machinery that recognize and respond to these marks, are strongly associated with neurodevelopmental disorders leading to mental retardation.

Mental retardation is characterized by an impairment of intellectual abilities, and by severe deficits in the capacity to adapt to the environment and the social milieu (American Psychiatric Association, 1994). The high prevalence of mental retardation worldwide (2.3%), and its strong familial and societal impact, make it of extreme importance to investigate its mechanisms and find new avenues towards its potential prevention and treatment. Mental retardation is a feature expressed in several neurodevelopmental disorders including Rett syndrome, Fragile X, and Down syndrome. Although its causes have not been clearly identified, its potential underlying mechanisms have been linked to epigenetic alterations. These alterations of the epigenome may be due to duplications or loss-of-function mutations in key components of the epigenetic machinery, particularly those involved in reading and interpreting the epigenetic code, or to anomalies of the epigenetic marks themselves. These two mechanisms are not mutually exclusive, since impaired functions of core genes that regulate the epigenome can have a dramatic effect on the epigenetic profile. Interestingly, severe mental retardation is one of the major characteristics of imprinting disorders, that result from aberrant chromosomal marks in genes normally expressed monoallelically from either the maternal or paternal copy depending on its epigenetic state. These disorders are thought to result from errors in the erasure, the establishment, or the maintenance of imprints leading to aberrant expression of imprinted genes. Many of the genes involved in mental retardation are located on the X-chromosome (Jensen et al., 2011),

Section snippets

Misinterpretation of epigenetic marks

The posttranslational modification (PTM) of histone proteins in the chromatin is an important mechanism for the epigenetic marking of the genome. Histone PTMs are varied and co-occur in complex combinations on individual histones and in different nucleosomes. Because their combinations are not random but appear to follow specific rules, it was proposed that they form a “histone code” (Strahl & Allis, 2000). According to this concept, histone PTMs are established in a specific manner through

Abnormal epigenetic marks

A normal epigenetic profile is necessary for a gene to be correctly transcribed. An altered DNA methylation or an abnormal profile of histone PTM can have profound effects on gene expression and alter cellular functions. Here, we describe how altered epigenetic marks may contribute to the pathogenesis of mental retardation.

Using DNA methylation patterns to diagnose diseases associated with mental retardation

The use of epigenetic markers has long been applied to cancer, and the number of markers of susceptibility, likelihood of transformation from precancerous lesions to cancerous lesions, prognosis markers, as well as diagnostic markers has increased tremendously (Deng, Liu, & Du, 2010). DNA methylation signatures in cancerous tissue after surgical extraction can be used as epigenetic biomarkers. For example, methylation of the CpG island surrounding exon 4 in Septin9, is increased in colorectal

Conclusions

Epigenetic anomalies seem to be a common thread in the pathogenesis of mental retardation. Many syndromes associated with mental retardation appear to be the result of loss-of-function mutations in single genes, suggesting that gene-therapy approaches may be beneficial. However, this type of therapy in humans is not yet feasible. Rather, the potential usage of DNMT and HDAC inhibitors is likely to be a focus for pharmacological interventions used to treat mental retardation, as has been already

Acknowledgments

The lab of IMM is funded by the University Zürich, the Swiss Federal Institute of Technology Zürich, the Swiss National Foundation, the National Center for Competence in Research “Neural Plasticity and Repair”, Roche.

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