title: Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males.
abstract: Loss-of-function mutations of the MECP2 gene at Xq28 are associated with Rett syndrome in females and with syndromic and nonsyndromic forms of mental retardation (MR) in males. By array comparative genomic hybridization (array-CGH), we identified a small duplication at Xq28 in a large family with a severe form of MR associated with progressive spasticity. Screening by real-time quantitation of 17 additional patients with MR who have similar phenotypes revealed three more duplications. The duplications in the four patients vary in size from 0.4 to 0.8 Mb and harbor several genes, which, for each duplication, include the MR-related L1CAM and MECP2 genes. The proximal breakpoints are located within a 250-kb region centromeric of L1CAM, whereas the distal breakpoints are located in a 300-kb interval telomeric of MECP2. The precise size and location of each duplication is different in the four patients. The duplications segregate with the disease in the families, and asymptomatic carrier females show complete skewing of X inactivation. Comparison of the clinical features in these patients and in a previously reported patient enables refinement of the genotype-phenotype correlation and strongly suggests that increased dosage of MECP2 results in the MR phenotype. Our findings demonstrate that, in humans, not only impaired or abolished gene function but also increased MeCP2 dosage causes a distinct phenotype. Moreover, duplication of the MECP2 region occurs frequently in male patients with a severe form of MR, which justifies quantitative screening of MECP2 in this group of patients.
authors.affiliation: Centre for Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium. Hilde.VanEsch@med.kuleuven.ac.be
authors.forename: Hilde
authors.initials: H
authors.lastname: Van Esch
authors.forename: Marijke
authors.initials: M
authors.lastname: Bauters
authors.forename: Jaakko
authors.initials: J
authors.lastname: Ignatius
authors.forename: Mieke
authors.initials: M
authors.lastname: Jansen
authors.forename: Martine
authors.initials: M
authors.lastname: Raynaud
authors.forename: Karen
authors.initials: K
authors.lastname: Hollanders
authors.forename: Dorien
authors.initials: D
authors.lastname: Lugtenberg
authors.forename: Thierry
authors.initials: T
authors.lastname: Bienvenu
authors.forename: Lars Riff
authors.initials: LR
authors.lastname: Jensen
authors.forename: Jozef
authors.initials: J
authors.lastname: Gecz
authors.forename: Claude
authors.initials: C
authors.lastname: Moraine
authors.forename: Peter
authors.initials: P
authors.lastname: Marynen
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Fryns
authors.forename: Guy
authors.initials: G
authors.lastname: Froyen
mesh_terms: D041321:Chromosomes, Human, X / Q000235:genetics*; D017931:DNA Primers; D018628:Gene Dosage / Q000235:genetics; D020440:Gene Duplication; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D009693:Nucleic Acid Hybridization; D010375:Pedigree
chemical_list: D017931:DNA Primers; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2