title: Spontaneous recurrent mutations and a complex rearrangement in the MECP2 gene in the light of current models of mutagenesis.
abstract: Mutations in the methyl-CpG-binding protein 2 (MECP2) gene are associated with Rett syndrome (RTT). The MECP2 gene has some unique characteristics: (1) it is mainly affected by de novo mutations, due to recurrent independent mutational events in a defined "hot spot" regions or positions; (2) complex mutational events along a single allele are frequently found in this gene; (3) most mutations arise on paternal X chromosome. The recurrent point mutations involve mainly CpG dinucleotides, where C>T transitions are explained by methylation-mediated deamination. The complex mutational events might be explained by the genomic architecture of the region involving the MECP2 gene. The finding that most spontaneous mutations arise on paternal X-chromosome supports the higher contribution of replication-mediated mechanism of mutagenesis. We present 9 types of mutations in the MECP2 gene, detected in a group of 22 Bulgarian and 6 Romanian classical RTT patients. Thirteen patients were clarified on molecular level (46.4%). The point mutations in our sample account for 61.5%. One intraexonic deletion was detected in the present study (7.7%). One novel insertion c.321_322insGAAG, p.(Lys107_Leu108insGluAlafs2*) was found (7.7%). Large deletions and complex mutations account for 23%. A novel complex mutational event c.[584_624del41insTT; 638delTinsCA] was detected in a Romanian patient. We discuss different types of the MECP2 mutations detected in our sample in the light of the possible mechanisms of mutagenesis. Complex gene rearrangements involving a combination of deletions and insertions have always been most difficult to detect, to specify precisely and hence to explain in terms of their underlying mutational mechanisms.
authors.affiliation: Department of Medical Chemistry and Biochemistry, Sofia Medical University, Sofia, Bulgaria.
authors.forename: Tihomir
authors.initials: T
authors.lastname: Todorov
authors.forename: Albena
authors.initials: A
authors.lastname: Todorova
authors.forename: Cristina
authors.initials: C
authors.lastname: Motoescu
authors.forename: Petia
authors.initials: P
authors.lastname: Dimova
authors.forename: Daniela
authors.initials: D
authors.lastname: Iancu
authors.forename: Dana
authors.initials: D
authors.lastname: Craiu
authors.forename: Daniela
authors.initials: D
authors.lastname: Stoian
authors.forename: Ligia
authors.initials: L
authors.lastname: Barbarii
authors.forename: Veneta
authors.initials: V
authors.lastname: Bojinova
authors.forename: Vanyo
authors.initials: V
authors.lastname: Mitev
mesh_terms: D001483:Base Sequence; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D015518:Rett Syndrome / Q000235:genetics*; D014178:Translocation, Genetic
chemical_list: C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2