Effects of MECP2 mutation type, location and X-inactivation in modulating Rett syndrome phenotype.
Rett syndrome (RTT) is a clinically defined disorder that describes a subset of patients with mutations in the X-linked MECP2 gene. However, there is a high degree of variability in the clinical phenotypes produced by mutations in MECP2, even amongst classical RTT patients. In a large-scale screening project, this variability has been examined by looking at the effects of mutation type, functional domain affected and X-inactivation. Mutations have been identified in 60% of RTT patients in this study (25% of whom were atypical), including 23 novel mutations and polymorphisms. More mutations were found in classical patients (63%) compared to atypical patients (44%). All of the pathogenic mutations were de novo in patients for whom parent DNA was available for screening. A composite phenotype score was developed, based on the recommendations for reporting clinical features in RTT of an international collaborative group. This score proved useful for summarising phenotypic severity, but did not correlate with mutation type, domain affected or X-inactivation, probably due to complex interactions between all three. Other correlations suggested that truncating mutations and mutations affecting the methyl-CpG-binding domain tend to lead to a more severe phenotype. Skewed X-inactivation was found in a large proportion (43%) of our patients, particularly in those with truncating mutations and mutations affecting the MBD. It is therefore likely that X-inactivation does modulate the phenotype in RTT.
Weaving
Linda S
LS
Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, Australia.
Williamson
Sarah L
SL
Bennetts
Bruce
B
Davis
Mark
M
Ellaway
Carolyn J
CJ
Leonard
Helen
H
Thong
Meow-Keong
MK
Delatycki
Martin
M
Thompson
Elizabeth M
EM
Laing
Nigel
N
Christodoulou
John
J
D001315:Australia; D002868:Chromosomal Proteins, Non-Histone; D018389:Codon, Nonsense; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D019992:Databases as Topic; D004303:Dosage Compensation, Genetic; D016368:Frameshift Mutation; D005838:Genotype; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2; D016254:Mutagenesis, Insertional; D009154:Mutation; D010641:Phenotype; D011110:Polymorphism, Genetic; D012097:Repressor Proteins; D015518:Rett Syndrome / Q000235:genetics* / Q000473:pathology; D017384:Sequence Deletion
D002868:Chromosomal Proteins, Non-Histone; D018389:Codon, Nonsense; D004268:DNA-Binding Proteins; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D012097:Repressor Proteins; D004247:DNA