title: Effects of MECP2 mutation type, location and X-inactivation in modulating Rett syndrome phenotype.
abstract: 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.
authors.affiliation: Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, Australia.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Weaving
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Williamson
authors.forename: Bruce
authors.initials: B
authors.lastname: Bennetts
authors.forename: Mark
authors.initials: M
authors.lastname: Davis
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Ellaway
authors.forename: Helen
authors.initials: H
authors.lastname: Leonard
authors.forename: Meow-Keong
authors.initials: MK
authors.lastname: Thong
authors.forename: Martin
authors.initials: M
authors.lastname: Delatycki
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Thompson
authors.forename: Nigel
authors.initials: N
authors.lastname: Laing
authors.forename: John
authors.initials: J
authors.lastname: Christodoulou
mesh_terms: 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
chemical_list: 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