Molecular genetics of Rett syndrome: when epigenetic signals go unrecognized

Rett syndrome (RTT) is an X-linked progressive neurodevelopmental disorder causing mental retardation mainly in girls. Affected patients are characterized by a period of normal development followed by a rapid regression phase that leaves them with a profound mental handicap. Mutations in the MECP2 gene, coding for a transcriptional repressor involved in chromatin remodeling, are the primary cause of Rett syndrome but are also found in patients affected by learning disability, neonatal encephalopathy, autism and mental retardation therefore making RTT paradigmatic for the study of autism spectrum disorders. Recent experiments indicate that MeCP2-deficient neurons are not permanently damaged, since Mecp2 reactivation leads to robust abrogation of advanced neurological defects in both young and adult animals. Although these results do not provide immediate therapeutic strategies for RTT, they establish the principle of reversibility of RTT and related disorders suggesting the necessity to develop therapeutical approaches. In this communication we will summarize the fundamental discoveries of the last 9 years relevant to MeCP2 related neurological disorder and we will discuss the new challenges inspired by these discoveries. In particular, we will underline the importance of the identification of the critical factors that function downstream of MeCP2 as well as of the modifier genes that subdue the disease symptoms. As Huda Zhogbi wrote “RTT story started in the clinic, but today has inspired many exciting basic science studies in neurobiology and epigenetics. It is anticipated that the next chapter in this story will involve translating some of the discoveries back to the clinic to benefit patients with RTT and patients with related neurological disorders”.