PMID- 29431277
OWN - NLM
STAT- MEDLINE
DCOM- 20190513
LR  - 20190513
IS  - 1098-1004 (Electronic)
IS  - 1059-7794 (Linking)
VI  - 39
IP  - 5
DP  - 2018 May
TI  - MeCP2 AT-Hook1 mutations in patients with intellectual disability and/or 
      schizophrenia disrupt DNA binding and chromatin compaction in vitro.
PG  - 717-728
LID - 10.1002/humu.23409 [doi]
AB  - 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.
CI  - (c) 2018 Wiley Periodicals, Inc.
FAU - Sheikh, Taimoor I
AU  - Sheikh TI
AD  - Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health 
      Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, 
      Canada.
AD  - Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
FAU - Harripaul, Ricardo
AU  - Harripaul R
AD  - Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health 
      Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, 
      Canada.
AD  - Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
FAU - Ayub, Muhammad
AU  - Ayub M
AD  - Lahore Institute of Research & Development, Lahore, Pakistan.
AD  - Department of Psychiatry, Queen's University, Kingston, Ontario, Canada.
FAU - Vincent, John B
AU  - Vincent JB
AUID- ORCID: 0000-0003-0692-2519
AD  - Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health 
      Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, 
      Canada.
AD  - Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
AD  - Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180308
PL  - United States
TA  - Hum Mutat
JT  - Human mutation
JID - 9215429
RN  - 0 (Chromatin)
RN  - 0 (Methyl-CpG-Binding Protein 2)
RN  - 9007-49-2 (DNA)
RN  - Rett Syndrome, Atypical
SB  - IM
MH  - *AT-Hook Motifs
MH  - Adult
MH  - Animals
MH  - Base Sequence
MH  - Cell Line
MH  - Chromatin/*metabolism
MH  - Computer Simulation
MH  - DNA/genetics/*metabolism
MH  - DNA Mutational Analysis
MH  - Female
MH  - Humans
MH  - Intellectual Disability/*genetics
MH  - Male
MH  - Methyl-CpG-Binding Protein 2/*chemistry/*genetics
MH  - Mice
MH  - Middle Aged
MH  - Mutation/*genetics
MH  - Pedigree
MH  - Protein Domains
MH  - Rett Syndrome/genetics
MH  - Schizophrenia/*genetics
OTO - NOTNLM
OT  - AT-Hook domain
OT  - EMSA
OT  - MeCP2
OT  - chromatin
OT  - intellectual disability
OT  - schizophrenia
EDAT- 2018/02/13 06:00
MHDA- 2019/05/14 06:00
CRDT- 2018/02/13 06:00
PHST- 2017/11/01 00:00 [received]
PHST- 2018/01/10 00:00 [revised]
PHST- 2018/02/07 00:00 [accepted]
PHST- 2018/02/13 06:00 [pubmed]
PHST- 2019/05/14 06:00 [medline]
PHST- 2018/02/13 06:00 [entrez]
AID - 10.1002/humu.23409 [doi]
PST - ppublish
SO  - Hum Mutat. 2018 May;39(5):717-728. doi: 10.1002/humu.23409. Epub 2018 Mar 8.