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Human Molecular Genetics Advance Access originally published online on September 22, 2004
Human Molecular Genetics 2004 13(21):2547-2555; doi:10.1093/hmg/ddh296
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Human Molecular Genetics, Vol. 13, No. 21 © Oxford University Press 2004; all rights reserved

Somatic mosaicism in patients with Angelman syndrome and an imprinting defect

Hülya Nazlican1, Michael Zeschnigk1, Uwe Claussen2, Susanne Michel2, Stefan Boehringer1, Gabriele Gillessen-Kaesbach1, Karin Buiting1,* and Bernhard Horsthemke1

1Institut für Humangenetik, Universitätsklinikum Essen, Germany and 2Institut für Humangenetik, Universität Jena, Germany

Received August 13, 2004; Revised September 8, 2004; Accepted September 14, 2004

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.

* To whom correspondence should be addressed at: Institut für Humangenetik, Universitätsklinikum Essen, Hufelandtrasse 55, G-45122 Essen, Germany. Tel: +49 2017234555; Fax: +49 2017235900; Email: karin.buiting{at}uni-essen.de


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