A mutation-led search for novel functional domains in MeCP2
biorxiv(2018)
摘要
Most missense mutations causing Rett syndrome affect domains of MeCP2 that have been shown to either bind methylated DNA or interact with a transcriptional co-repressor complex. Several mutations, however, including the C-terminal truncations that account for ~10% of cases, fall outside these characterised domains. We studied the molecular consequences of four of these “non-canonical” mutations in cultured neurons and mice to see if they reveal additional essential domains without affecting known properties of MeCP2. The results show that the mutations partially or strongly deplete the protein and also in some cases interfere with co-repressor recruitment. These mutations therefore impact the activity of known functional domains and do not invoke new molecular causes of Rett syndrome. The finding that a stable C-terminal truncation does not compromise MeCP2 function raises the possibility that small molecules which stabilise these mutant proteins may be of therapeutic value.
* CTD
: C-terminal deletion
DAPI
: 4’,6-diamidino-2-phenylindole dihydrochloride
EGFP
: enhanced green fluorescent protein
ES
: cells embryonic stem cells
ExAC
: Exome Aggregation Consortium
FACS
: fluorescence activated cell sorting
LUHMES
: Lund human mesencephalic cells
MBD
: methyl-binding domain
NID
: NCoR/SMRT-interacting domain
PBS
: phosphate-buffered saline
RA
: retinoic acid
RTT
: Rett syndrome
WT
: wild-type
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