Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2

Abstract

Rett syndrome (RTT, MIM 312750) is a progressive neurodevelopmental disorder and one of the most common causes of mental retardation in females, with an incidence of 1 in 10,000-15,000 (ref. 2). Patients with classic RTT appear to develop normally until 6-18 months of age, then gradually lose speech and purposeful hand use, and develop microcephaly, seizures, autism, ataxia, intermittent hyperventilation and stereotypic hand movements. After initial regression, the condition stabilizes and patients usually survive into adulthood. As RTT occurs almost exclusively in females, it has been proposed that RTT is caused by an X-linked dominant mutation with lethality in hemizygous males. Previous exclusion mapping studies using RTT families mapped the locus to Xq28 (refs 6,9,10,11). Using a systematic gene screening approach, we have identified mutations in the gene (MECP2 ) encoding X-linked methyl-CpG-binding protein 2 (MeCP2) as the cause of some cases of RTT. MeCP2 selectively binds CpG dinucleotides in the mammalian genome and mediates transcriptional repression through interaction with histone deacetylase and the corepressor SIN3A (refs 12,13). In 5 of 21 sporadic patients, we found 3 de novo missense mutations in the region encoding the highly conserved methyl-binding domain (MBD) as well as a de novo frameshift and a de novo nonsense mutation, both of which disrupt the transcription repression domain (TRD). In two affected half-sisters of a RTT family, we found segregation of an additional missense mutation not detected in their obligate carrier mother. This suggests that the mother is a germline mosaic for this mutation. Our study reports the first disease-causing mutations in RTT and points to abnormal epigenetic regulation as the mechanism underlying the pathogenesis of RTT.

Neuroinflammation: Ways in Which the Immune System Affects the Brain

“…Given that many neurodevelopmental and/or neuropsychiatric disorders (e.g., autism, schizophrenia) have now been associated with abnormalities in synaptic circuits and glial cells, it was hypothesized that microglia-synapse interactions in the developing brain could be disrupted and underlie abnormalities in the synaptic circuitry in these disorders. Rett syndrome, a neurodevelopmental disorder that primarily affects girls, is caused by mutations in a global regulator of chromatin remodeling and gene transcription, methyl CpG-binding protein 2, in >95 % of cases [40,41]. In a mouse model of this disorder (MeCP2-null), RGC synapse remodeling is abnormal [42].…”

Familial cases and male cases with MECP2 mutations

“…MECP2 gene was sequenced as previously described (Amir et al, 1999). Evaluations on large deletions and duplications were performed using the MLPA‐P015 probe (SALSA MLPA kitP015 MECP2 , MRC‐Holland, Amsterdam, Holland).…”

“…Mutations of the gene encoding methyl‐CpG‐binding protein 2 ( MeCP2 ), located at Xq28, are responsible for causing most cases of RTT (Amir et al, 1999). MeCP2 is a key protein in the brain, acting as a transcriptional repressor and an activator for genes associated with normal nerve cell function (Chahrour et al, 2008).…”

Early development in Rett syndrome – the benefits and difficulties of a birth cohort approach

“…1–4 The natural history of this disorder follows a four-stage trajectory including a period of regression with subsequent recovery or stabilization. 3,5 Hagberg 5 reported on 35 females characterized inter alia by loss of verbal communicative abilities and purposeful hand use with simultaneously occurring hand stereotypies (hand wringing, washing character).…”

“…6 Since then, consensus clinical criteria have been developed and constantly modified according to the scientific and clinical advances in the study of RTT. 4,7 The main mutation responsible for this clinical condition was discovered more than 30 years after its first description, 1 and a classification system differentiating between typical RTT and atypical RTT (or RTT variants, such as preserved speech variant, early seizure variant, congenital variant) has been established. 4,8 In recent years, numerous studies on the aetiology of the disorder, the epidemiology, the treatment, and potential advances in facilitating earlier diagnosis have been conducted.…”