The Role of Imprinting Defects in Angelman Syndrome, Autism, and Other Disorders (PDF - 1.13 MB)
Dr. Arthur Beaudet, Department of Molecular & Human Genetics, Baylor College of MedicineHouston, Texas
My laboratory has studied Prader-Willi syndrome (PWS) and Angelman syndrome (AS) for many years. We define a genetic condition as one caused by an abnormality of nucleotide sequence, and an epigenetic condition as one caused by an abnormality of gene expression not accompanied by a change in nucleotide sequence. By these definitions, the common 15q11-q13 deletion form of AS is a genetic condition, and the paternal UPD 15 form of AS is an epigenetic condition. Our studies of genetic and epigenetic phenotypes have led us to propose that overexpression of the Angelman gene (UBE3A) may be the most common cause of autism. Autism is commonly considered to be caused by the interaction of susceptibility alleles at 10 or more loci, largely because the concordance for monozygotic twins is high, while that for dizygotic twins is low, and because genome-wide linkage studies have not identified autism-related genes. Rather than 10 or more loci, we propose that the twin data could be consistent with one principal locus subject to de novo imprinting defects arising in germ cells or early embryos at a stage prior to that of monozygous twinning. Based on maternal duplications of chromosome 15q causing autism, evidence for allele sharing in 15q among sibling pairs, tissue-specific differential methylation in 15q, abnormalities of DNA methylation in some autism brains, and MTHFR association studies, we propose a mixed epigenetic and genetic model for autism with both de novo and inherited contributions. The MTHFR results raise the question of whether folic acid intake by either parent may alter the risk of imprinting defects. We suggest that the Angelman gene (UBE3A), which encodes an ubiquitin ligase, may, through overexpression or dysregulation, also be the principal autism gene.
Not directly related to our work but of great importance for this conference is the concern that intracytoplasmic sperm injection may cause imprinting defects leading to Angelman syndrome and Beckwith-Wiedemann syndrome.