Genetic Imprinting in Human Genetics

A series of studies led by Dr. Marc Lalande, formerly of this IDDRC, delineated the regions on chromosome 15q11-13 that are mutated in Angelman syndrome (AS) and Prader-Willi syndrome (PWS). Lalande’s research also identified candidate genes in these regions and provided important insights into how an abnormality in genetic imprinting can lead to mental retardation (Am. J. Hum. Genet., 1991; Genomics, 1991; Lancet, 1992; Nature Genetics, 1992; Hum. Molec. Genet., 1993; Am. J. Med. Gen., 1993; Nature Genetics, 1994; Am. J. Med. Gen., 1994). The majority of the AS and PWS patients display a cytogenetic deletion of chromosome 15q11-q13. The deletions of 15q11-q13 in AS occur exclusively on the chromosome inherited from the mother whereas the deleted chromosome 15 in PWS is always of paternal origin. This marked difference in the parental origin of the deletions is consistent with the hypothesis that imprinting is involved in the etiology of AS and PWS. The occurrence of uniparental disomy in some patients with no cytogenetic deletion further supports the hypothesis that chromosome 15q11-q13 is an imprinted region. A cluster of genes encoding ?-aminobutyric acid (GABAA) receptor subunits were mapped to this region and thought to play a role in the genesis of the epilepsy characteristic of this disorder. This work has continued in our IDDRC and led to the identification of the principal gene affected in AS, the ubiquitin ligase ube3a. Current work in the IDDRC by Greenberg and his colleagues has shown that ube3a functions to regulate synapse number during development.