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.

Angelman syndrome imprinting center encodes a transcriptional promoter

“…Mosaicism is detected in about 30% of individuals diagnosed with AS-imprinting defects (35,36). These are presumably cases in which the imprint was lost postfertilization.…”

Clinical and genetic aspects of Angelman syndrome

“…44,48 Individuals with an imprinting defect (ID) or with UPD have higher developmental and language ability than those with other underlying molecular mechanisms. Individuals who are mosaic for the nondeletion ID (approximately 20% of the ID group) have the most advanced speech abilities 49 ; they may speak up to 50 -60 words and use simple sentences. These individuals may not be suspected initially to have AS because their gait may not appear abnormal and their speech ability may seem too advanced, thus appropriate diagnostic testing may not be requested.…”

Molecular and Clinical Aspects of Angelman Syndrome

“…Soon after this discovery, those with the deletion were compared to those without the microdeletion. As additional AS-causing mechanisms were identified, the clinical correlations became more complicated because of overlapping symptoms among all mechanisms [Saitoh et al, 1994;Smith et al, 1997;Fridman et al, 2000;Lossie et al, 2001;Nazlican et al, 2004;Saitoh et al, 2005]. It soon became evident that the core features of the syndrome can be attributed solely to disruption of the UBE3A gene, regardless of the mechanism, but some differences did exist among the genetic types.…”

“…These individuals may speak up to 50-60 words and use simple sentences [Nazlican et al, 2004]. However, this degree of expressive language in AS is rare.…”