Rett Syndrome Flashcards
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
Bidirectional sequencing of mecp2 detects what % of classic and atypical rett?
85-90% of classic and 30-40% atypical
When should u check primers for snps?
Each time data base is updated
Testing strategy
1) pcr conditions same for 2-4 but dif for 1
2) primers tagged and sequencing carried out using abi big dye terminator kit and run on abi 3130
3) data analysed using MS by comparing test and control. Genbank files used and annotated. Rob defined.
4) MLPA kit from MRC holland used.
If a pathogenic variant is identified what should u do?
Request parental DNA
Offer testing to all female relatives of pro and
Offer testing to males with possible rett phenotype
What is skewed x inactivation?
When by chance more than half of cells have chromosome bearing normal genes
How to test for x inactivation?
1) Pcr polymorphic CAG repeat in the first exon of the androgen receptor gene (AR)
2) DNA cut with methylation sensitive restriction enzymes HpaII and CfoI
3) look for quantitative skew eg 75:25
What gene can be tested if patient has atypical Rett syndrome? What phenotype is found in all patients with a mutation in this gene?
Cdkl5
. Seizures before 6 months
What gene involved in the development of the central nervous system is also a candidate for atypical rett? (Only 1 case)
NTNG1= chromosome 1. 340kb, 10 exons (9 coding)
What gene causes congenital form of Rett ( presenting in first few month of life)
FOXG1 (14q13)
Phenotype for SLC9A6 mutations
Found in x- linked mental retardation., microcephaly, epilepsy and phenotype mimicking angelman syndrome
Frequency of Rett syndrome?
1:10,000 by the age of 12
Clinical features of Rett?
- Severe neurodevelopment disorder
- Normal early development followed by loss of fine and gross motor skills
- characteristic stereotypic hand movements
