A novel mutation R190H in the AT-hook 1 domain of MeCP2 identified in an atypical Rett syndrome

Zhou, Xiao; Liao, Yuangao; Xu, Miaojing; Ji, Zhong; Xu, Yunqi; Zhou, Liang; Wei, Xiaoming; Hu, Peiqian; Han, Peng; Yang, Fanghan; Pan, Suyue; Y, Hu

doi:10.18632/oncotarget.18955

Cited by 10 publications

(10 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, the missense variant NM_004992.3:c.554G > T; p.(Gly185Val) was identified in two brothers with intellectual disability with regression of language and autism spectrum disorder (Bianciardi et al., ). Also recently, p.Arg190His has recently been reported in a Chinese girl with regression and late onset cognitive decline (Zhou et al., ). Some of these variants have been demonstrated to have less severe consequences at the molecular and cellular level, in comparison with Rett mutations (Sheikh et al., ).…”

Section: Discussionmentioning

confidence: 90%

“…(2017). Clinical characteristics for PK55 family members, for a girl with atypical RTT also with the p.(Arg190His) mutation (de novo; (Zhou et al., )) and for a female affected with SCZ reported to have the de novo mutation chrX:153296711G > A; NM_004992.3: c.568C > T; p.(Arg190Cys) (McCarthy et al., ), are summarized in Table . More detailed clinical descriptions are provided in Supplementary Information.…”

Section: Resultsmentioning

confidence: 99%

“…In particular, substitutions that are not known to cause RTT, and may represent hypomorphic alleles. Here, we studied functional effects of a MECP2 AT‐Hook1 mutation (p.(Arg190His)) identified in a large consanguineous family with cognitive disability and SCZ (Harripaul et al., 2017) and in a girl with atypical RTT (Zhou et al., ), and another reported mutation p.(Arg190Cys) (McCarthy et al., ), that affect AT‐rich DNA‐binding and chromatosome condensation. In addition, we have also developed a new, simple and rapid method to quantify the DNA‐protein interaction.…”

Section: Discussionmentioning

confidence: 99%

“…Here, we studied the functional consequences of MECP2‐AT‐Hook1 domain mutation (chrX:153296710C>T; NM_004992.3:c.569G > A; p.(Arg190His)), which we previously identified in a large consanguineous family with many individuals affected with cognitive decline with or without childhood onset SCZ (Figure ) (Harripaul et al., 2017), and reported as de novo in a girl with atypical RTT (Zhou et al., ). Our investigations show the negative effect of this mutation, as well as a de novo mutation (chrX:153296711G > A; NM_004992.3: c.568C > T; p.(Arg190Cys)) in a female with SCZ, on DNA binding of the MECP2 AT‐Hook 1 domain.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

MeCP2 AT-Hook1 mutations in patients with intellectual disability and/or schizophrenia disrupt DNA binding and chromatin compaction in vitro

et al. 2018

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

MeCP2 AT-Hook1 mutations in patients with intellectual disability and/or schizophrenia disrupt DNA binding and chromatin compaction in vitro

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Moreover, most MeCP2 binding sites are in intronic regions between transcription units and outside of CPG islands [11]. MeCP2 acts as a transcription inhibitor, and its TRD domain can bind to the AThook of the target gene to inhibit transcription [11][12][13]. MeCP2 can also recruit CBER to form a coactivator that activates the transcription of downstream genes [14].…”

Section: Introductionmentioning

confidence: 99%

Transcriptome Analysis of Brain Tissues in a MeCP2-Null Rat Model of Rett Syndrome

Liu¹,

Fu²,

X³

et al. 2019

Preprint

View full text Add to dashboard Cite

Objective: Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in MeCP2, a transcription factor. MeCP2 mutations cause abnormal expression of downstream genes and eventually lead to brain dysfunction. The role of MeCP2 in brain neural development remains unclear. To further elucidate this role, a MeCP2-null rat model was created with the CRISPR/cas9 system. Method: A MeCP2-cas9 vector was constructed and then microinjected into fertilized rat ova in vitro. Two mutations by CRISPR/cas9 were confirmed to cause deletions in exon 2 of MeCP2 via DNA sequencing, and protein expression was measured by Western blotting. Transcriptome data for three brain tissues, the cerebellum, cerebral cortex and hippocampus, were obtained via next-generation sequencing. Results: MeCP2-null rats were successfully obtained, and preliminary analysis showed that the MeCP2-null rats exhibited motor dysfunction and anxious and depressed behaviour. In addition, differentially expressed genes (DEGs) were identified in the three MeCP2-null brain tissues compared to wild-type rat brain tissues. In the rat cerebellum, 388 downregulated DEGs were mainly involved in the calcium ion signalling pathway and the PI3K-Akt signalling pathway. In the cerebral cortex, 386 upregulated DEGs were primarily involved in intracellular signal transduction, protein phosphorylation and the MAPK signalling pathway. In the hippocampus, the DEGs were related to the MAPK signalling pathway. Conclusion: We constructed a MeCP2-null rat model with unique features with CRISPR/cas9 technology to study RTT and analysed DEGs in three rat brain tissues to highlight potential targets for the development of new medicines.

show abstract

Disruption of AT-hook 1 domain in MeCP2 protein caused behavioral abnormality in mice

Xu¹,

Song²,

Huang³

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

View full text Add to dashboard Cite

MECP2 is the causative gene for autism spectrum disorders, including Rett syndrome, a regressive neurodevelopmental rare disease mainly occurring in girls. Except for the distinct methyl-CpG binding domain and the transcriptional repression domain in MeCP2, three AT-hook-like domains have recently been identified. Several mutations in AT-hook 1 domain have been reported in autism cases or Rett database. However, the role of AT-hook 1 domain is still unclear. In this study, we generated a mouse line carrying deletion of eight conserved amino acids in AT-hook 1 domain by clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology. Mecp2 mutant male mice exhibited low locomotor activity, motor incoordination and cognitive deficit. In addition, these mutant mice exhibited increased anxiety. Moreover, pain insensitivity was noted in the mutant males. However, the social interactions were unaffected in AT-hook 1 mutant mice. Thinner CA1 region of the hippocampus was observed in the mutant mice. On the molecular basis, Western blot analysis showed increased expression of mutant MeCP2 protein in the cortex. Additionally, several genes expressed specifically in inhibitory neurons were markedly changed in the cerebrum. Taken together, these data demonstrate that disruption of AT-hook 1 domain in MeCP2 caused behavioral abnormality in mice, which suggests that AT-hook 1 is a critical region for the function of MeCP2 protein.

show abstract

A novel mutation R190H in the AT-hook 1 domain of MeCP2 identified in an atypical Rett syndrome

Abstract: Background: Mutations in

Cited by 10 publications

References 32 publications

MeCP2 AT-Hook1 mutations in patients with intellectual disability and/or schizophrenia disrupt DNA binding and chromatin compaction in vitro

MeCP2 AT-Hook1 mutations in patients with intellectual disability and/or schizophrenia disrupt DNA binding and chromatin compaction in vitro

Transcriptome Analysis of Brain Tissues in a MeCP2-Null Rat Model of Rett Syndrome

Disruption of AT-hook 1 domain in MeCP2 protein caused behavioral abnormality in mice

Contact Info

Product

Resources

About

A novel mutation R190H in the AT-hook 1 domain of MeCP2 identified in an atypical Rett syndrome

Abstract: Background: Mutations in

Cited by 10 publications

References 32 publications

MeCP2 AT-Hook1 mutations in patients with intellectual disability and/or schizophrenia disrupt DNA binding and chromatin compaction in vitro

MeCP2 AT-Hook1 mutations in patients with intellectual disability and/or schizophrenia disrupt DNA binding and chromatin compaction in vitro

Transcriptome&nbsp;Analysis of Brain Tissues in a MeCP2-Null Rat Model of Rett Syndrome

Disruption of AT-hook 1 domain in MeCP2 protein caused behavioral abnormality in mice

Contact Info

Product

Resources

About

Transcriptome Analysis of Brain Tissues in a MeCP2-Null Rat Model of Rett Syndrome