Rett Syndrome Flashcards
What gene is affected in Rett syndrome?
- MECP2
- Mutations identified in 80-95% females with classic Rett syndrome
- In 99.5% of cases the mutations are single occurrences
- Mostly females affected, parents can be germline mosaics and the degree of presentation in a female can be affected by the level of skewed X inactivation
- Exon 1 discovered in 2004 - total of 4 exons
Who is mostly affected by Rett syndrome?
- Mostly females affected, parents can be germline mosaics and the degree of presentation in a female can be affected by the level of skewed X inactivation
How many exons does MECP2 contain?
- Exon 1 discovered in 2004 - total of 4 exons
How many mutations have been found in MECP2?
about 390 (RettBASE)
Describe the mutation spectrum of MECP2
- Approximately 390 reported pathogenic mutations found in MECP2.
- Most cases are sporadic with approximately 95% of cases being caused by a de novo mutation on the paternal copy of MECP2.
- Screening of Rett patients has shown that 90-95% will have a pathogenic mutation - 8 common mutations that account for 70% of these and a further 9% are a result of small deletions in a c-terminal hot spot.
- Mutations in exons 3-4 account for about 80% of classic Rett, 50% for the preserved speech variant of atypical Rett syndrome and lower percentages for other atypical variants
- Large deletions have been found in classical and atypical Rett and frequently involve exons 3 and 4. This is probably as a result of unequal recombination as there are two highly repetitive regions, one in exon 4 and the other in intron 2. Recombination between these regions could lead to the deletion of exons 3 and 4.
- It has been suggested that de novo mutations occur in male germ cells resulting in affected daughters
- CpG dinucleotides are susceptible to mutations - in one study seven of the eight identified MECP2 variants involved a C to T transition at a CpG site.
- Large deletions are more commonly found in individuals with a classic Rett syndrome phenotype (30%) than an atypical phenotype (7%).
- Pathogenic mutations in exon 1 are rare. There have been no mutations identified in exon 2.
What % of Rett syndrome cases are caused by a de novo mutation on the paternal copy of MECP2?
Most cases are sporadic with approximately 95% of cases being caused by a de novo mutation on the paternal copy of MECP2
What % of classic Rett syndrome cases do mutations in MECP2 exons 3-4 account for?
Mutations in exons 3-4 account for about 80% of classic Rett, 50% for the preserved speech variant of atypical Rett syndrome and lower percentages for other atypical variants
What is thought to cause the large deletions in MECP2 exons 3 and 4 that are often observed in Rett syndrome patients?
Large deletions have been found in classical and atypical Rett and frequently involve exons 3 and 4. This is probably as a result of unequal recombination as there are two highly repetitive regions, one in exon 4 and the other in intron 2. Recombination between these regions could lead to the deletion of exons 3 and 4.
What exons are MECP2 mutations usually seen in?
- Mutations in exons 3-4 account for about 80% of classic Rett, 50% for the preserved speech variant of atypical Rett syndrome and lower percentages for other atypical variants.
- Pathogenic mutations in exon 1 are rare. There have been no mutations identified in exon 2.
Are MECP2 de novo mutations more likely to come from the maternal or paternal allele?
- It has been suggested that de novo mutations occur in male germ cells resulting in affected daughters.
- In a study of 19 Rett cases 70% of mutations were from the paternal allele. This may explain the high number of females seen with the condition and the lower number of males as the fathers will not pass their X chromosome onto their son.
What may explain the high number of females seen with the condition and the lower number of males?
- It has been suggested that de novo mutations occur in male germ cells resulting in affected daughters.
- In a study of 19 Rett cases 70% of mutations were from the paternal allele. This may explain the high number of females seen with the condition and the lower number of males as the fathers will not pass their X chromosome onto their son.
Where have missense mutations in MECP2 been identified?
Missense mutations have been found predominantly in the Methyl Binding Doman (MBD). This region binds symmetrically methylated CpGs.
Where have nonsense mutations in MECP2 been identified?
Nonsense mutations - more scattered between the Methyl Binding Domain (MBD) and the Transcription Repression Domain (TRD). TRD recruits co-suppressor complexes that mediates the repression of transcription.
Where have deletions in MECP2 been identified?
Deletions tend to be found in what is referred to as the ‘deletion prone region’ and almost all cause a loss of the terminal region of the protein. This region affects codons 366-388 and these small deletions make up about 7% of all MECP2 mutations.
What mutations are you most likely to find in the Methyl Binding Domain of MECP2?
Missense mutations have been found predominantly in the Methyl Binding Doman (MBD).
Nonsense mutations - more scattered between the Methyl Binding Domain (MBD) and the Transcription Repression Domain (TRD).
Describe the structural domains of MECP2.
There are 3 functional domains and a nuclear localisation signalling domain in MECP2.
1) . Methyl Binding Doman (MBD). This region binds symmetrically methylated CpGs.
2) . Transcription Repression Domain (TRD). TRD recruits co-suppressor complexes that mediates the repression of transcription.
3) . Tryptophan Tryptophan binding domain which is located closer to the C-terminus. This region binds splicing factors.
Describe what MECP2 mutations are seen in males.
- It was previously thought that mutations in MECP2 were lethal in males.
- 3 types of mutations are seen in males:
1) . Mutations that are found in classic Rett
2) . Mutations that are inherited from the mother which are not found in females with Rett. These have a range of MR severity with a good prognosis.
3) . Males with deletions of the whole MECP2 gene and neighbouring genes resulting in a severe phenotype.
- If the male is XXY or somatic mosaicism is present then a milder phenotype will be the result as the proportion of neurones carrying the mut will likely affect the phenotype.
- MECP2 in males can present as severe neonatal encephalopathy and affected individuals will usually die within the first few years of life. This led to the identification of a condition known as MECP2 duplication syndrome and this is the most common form of MECP2 mut found in males.
What is the most common form of MECP2 mutation found in males?
MECP2 in males can present as severe neonatal encephalopathy and affected individuals will usually die within the first few years of life. This led to the identification of a condition known as MECP2 duplication syndrome and this is the most common form of MECP2 mut found in males.
