Horsthemke, Bernhard; Wawrzik, Michaela; Groß, Stephanie; Lich, Christina; Sauer, Birgitta; Rost, Imma; Krasemann, Ernst; Kosyakowa, Nadezda; Liehr, Thomas; Weise, Anja; Dybowski, Jan Nikolaj; Hoffmann, Daniel; Wieczorek, Dagmar:

Parental origin and functional relevance of a de novo UBE3A variant.

In: European Journal of Medical Genetics, (2010) ; 54 (1), S. 19-24
ISSN: 1769-7212
Zeitschriftenaufsatz / Fach: Medizin; Informatik; Biologie
Sequence analysis of the imprinted UBE3A gene in a 3-year-old girl suspected of having Angelman syndrome had revealed a de novo 3 bp in frame deletion predicted to encode a protein lacking the amino acid G538 (based on sequence NM_130838). In order to assess the clinical relevance of this unknown variant, we determined the parental origin and the functional consequences of the deletion. We separated the two chromosomes 15 by microdissection of metaphase spreads and used cytogenetic and molecular markers to demonstrate that the deletion is on the maternal chromosome. For determining the functional consequences of the deletion, we modelled the structure of the deletion mutant based on the wildtype X-ray structure and simulated the molecular dynamics of the wildtype and mutant protein in complex with UcbH7. Our simulations showed that deletion of G538 destroys a network of salt bridges between highly conserved residues in the catalytic cleft of UBE3A. In conclusion, our results strongly suggest that the 3 bp deletion is a loss-of-function mutation of the maternal UBE3A allele that has caused Angelman syndrome in our patient. Our study may serve as a paradigm to determine the parental origin of a de novo mutation.