Effects of the parental origins of disease genes on the expression of inherited human disease have become increasingly apparent in recent years. These effects, in diseases such as Huntington's disease and myotonic dystrophy, have been attributed to differential activity of maternal versus paternal genes, or genetic imprinting. The research proposed here is a molecular genetic analysis of a region of human chromosome 15 that shows a striking parental origin effect. Deletions of the proximal long arm of the paternally-inherited chromosome 15 are found in Prader-Willi syndrome (PWS), characterized by hypotonia, obesity, and developmental delay. Patients with a distinct disorder, Angelman syndrome (AS), characterized by seizures, ataxia, developmental delay, and inappropriate laughter frequently show deletions of the same region of chromosome 15. However, in AS patients, the mutation is on the maternal chromosome. These observations suggest that one or more genes in this region is differentially expressed depending on parental origin. The proposed analysis includes construction of a physical map of the PWS-AS region by pulsed-field gel electrophoresis and cloning of candidate genes in the region. Identification of the gene or genes responsible for the phenotypes in PWS and AS promises to provide important insights into the control of gene expression during early development of the human nervous system.
| Wagstaff, J; Shugart, Y Y; Lalande, M (1993) Linkage analysis in familial Angelman syndrome. Am J Hum Genet 53:105-12 |
