title: Somatic mosaicism in patients with Angelman syndrome and an imprinting defect.
abstract: Angelman syndrome is a neurogenetic disorder caused by the loss of function of the imprinted UBE3A gene in 15q11-q13. In a small group of patients, the disease is due to an imprinting defect (ID) that silences the maternal UBE3A allele. The presence of a faint maternal band detected by methylation-specific PCR analysis of the SNURF-SNRPN locus in approximately one-third of patients who have an ID but no imprinting center deletion suggested that these patients are mosaics of ID cells and normal cells. In two patients studied, somatic mosaicism was proven by molecular and cellular cloning, respectively. X inactivation studies of cloned fibroblasts from one patient suggest that ID occurred before the blastocyst stage. To quantify the degree of mosaicism, we developed a novel quantitative methylation assay based on real-time PCR. In 24 patients tested, the percentage of normal cells ranged from <1% to 40%. Regression analysis suggests that patients with a higher percentage of normally methylated cells tend to have milder clinical symptoms than patients with a lower percentage. In conclusion, we suggest that the role of mosaic imprinting defects in mental retardation is underestimated.
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Hufelandtrasse 55, G-45122 Essen, Germany.
authors.forename: Hülya
authors.initials: H
authors.lastname: Nazlican
authors.forename: Michael
authors.initials: M
authors.lastname: Zeschnigk
authors.forename: Uwe
authors.initials: U
authors.lastname: Claussen
authors.forename: Susanne
authors.initials: S
authors.lastname: Michel
authors.forename: Stefan
authors.initials: S
authors.lastname: Boehringer
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.forename: Karin
authors.initials: K
authors.lastname: Buiting
authors.forename: Bernhard
authors.initials: B
authors.lastname: Horsthemke
mesh_terms: D017204:Angelman Syndrome / Q000235:genetics* / Q000503:physiopathology; D002478:Cells, Cultured; D003001:Cloning, Molecular; D018899:CpG Islands; D019175:DNA Methylation; D017931:DNA Primers; D004303:Dosage Compensation, Genetic; D005347:Fibroblasts / Q000378:metabolism; D051860:Fragile X Messenger Ribonucleoprotein 1; D018392:Genomic Imprinting; D006801:Humans; D018895:Microsatellite Repeats; D009030:Mosaicism; D009419:Nerve Tissue Proteins / Q000235:genetics; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D016601:RNA-Binding Proteins / Q000235:genetics; D012044:Regression Analysis; D017422:Sequence Analysis, DNA; D012867:Skin / Q000166:cytology
chemical_list: D017931:DNA Primers; D051860:Fragile X Messenger Ribonucleoprotein 1; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; C497683:FMR1 protein, human