Mutations in the methyl-CpG-binding protein-2 gene (MECP2) are commonly 
associated with Rett syndrome. However, it has long been appreciated that there 
exists a spectrum of neuropsychiatric phenotypes associated with MECP2 variants. 
The most frequent Rett missense mutations are located in either the 
methyl-CpG-binding domain (MBD) or transcription repression domain (TRD). 
Clinical roles for mutations in other domains such as the intervening domain 
(ID) or AT-Hook domains have yet to be determined. Here, we report functional 
analysis of MECP2 missense mutations, located in AT-Hook1 within the ID, in a 
large Pakistani family with childhood onset cognitive decline and schizophrenia 
(SCZ), de novo in a girl with atypical Rett syndrome, and de novo in a woman 
with SCZ. We show that both p.Arg190His and p.Arg190Cys affect the ability of 
MeCP2 to bind to AT-rich DNA, also the brain-derived neurotrophic factor (BDNF) 
promoter, with the more drastic effects seen for p.Arg190Cys. Both mutations 
also affect nuclear chromatin clustering in vitro. These data support a possible 
molecular link between MECP2 AT-Hook1 mutations and psychosis. Given the ongoing 
large-scale whole exome and whole genome sequencing projects for psychiatric 
disorders, our findings suggest that rare missense variants in MECP2 be 
carefully evaluated for molecular consequences.