Rett Syndrome Flashcards
(36 cards)
How many exon she in MECP2?
4
What % of females with classic rett have an mecp2 mutation?
80-95%
In 99.5% of cases they are de novo
How many reported pathogenic mutations?
~390 recorded in RettBase
What exons contain 80% of mutations?
3-4. But less for the preserved speech variant of atypical rett (~50%)
What is believed to cause the large deletions of exons 3 and 4 identified in typical and atypical rett ?
Highly repetitive sequences in exon 4 and intron 2 causing unequal recombination
What causes 71% of the de novo mutations found in female rett?
De novo mutations in male germ cells
Commonly caused by mutations to CpG dinucleotides ( many c>t)
What percentage of typical and atypical rett is caused by large mutations?
30% of classic and 7% of atypical
How common are mutations in cons 1 and 2?
Rare in exon 1 and to date none found in exon 2
How many domains in mecp2?
3 functional domains and a nuclear localisation domain
Where are Missense mutations most commonly found?
In methyl binding domain (mpd) it binds methylated CpGs
Where are nonsense mutations most commonly found?
Between MbD and transcription repression domain (trd) - recruits co-repressor complexes that mediate repression or transcription
Where are deletions usually found?
In the deletion prone region 336-388 codons
What are the 3 functional domains of mecp2?
1) MBD
2) TRD
3) tryptophan-tryptophan binding domain near the c-terminus that binds splicing factors
What 3 types of mutations are found in males?
1) mutations found in classic rett
2) mutations inherited from the mother which are not found in females with rett
3) males with deletions of entire genes and neighbouring genes resulting in severe phenotype
What is the most common mecp2 syndrome found in males?
Mecp2 duplication syndrome - severe neonatal encephalopathy baby dies within 2 years
How many meco2 isoforms are there?
2
What isoform is transcribed in the brain?
Mecp2-e1 contains exon1 but alternatively splices out exon 2 encoding a distinct n-terminus 490 aa
What isoform is found in fibroblast and lymphocyte cells?
Mecp2-e2 - doesn’t contain exon 1 but contains part of exon 2 486aa
Which isoform is more abundant ?
E1, e2 less easily transcribed
What is the believed to be the role of mecp2?
A global transcription repressor
May be linked to the regulation of transcription or synaptic activity
Phenotype of mutations 3’ to the TRD region ?
Milder phenotype probably due to late truncating protein formed
Phenotype of females with missense mutations ?
Significantly milder phenotype than those with nonsense/ frame shift mutations
Location of missense and truncating mutations?
Missense predominantly in MBD and truncating in TRD or 3’ end
Why are truncating mutations not found in MBD?
May be due to selection against as the phenotype may be too severe
