Journal Article

Somatic mosaicism in patients with Angelman syndrome and an imprinting defect

Hülya Nazlican, Michael Zeschnigk, Uwe Claussen, Susanne Michel, Stefan Boehringer, Gabriele Gillessen-Kaesbach, Karin Buiting and Bernhard Horsthemke

in Human Molecular Genetics

Volume 13, issue 21, pages 2547-2555
Published in print November 2004 | ISSN: 0964-6906
Published online September 2004 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddh296
Somatic mosaicism in patients with Angelman syndrome and an imprinting defect

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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.

Journal Article.  5532 words.  Illustrated.

Subjects: Genetics and Genomics

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