Genetic Imprinting in Prader-Willi and Angelman Syndromes
by Wendy A. Hiltunen

Normal development requires genes to be inherited from both parents. Genetic imprinting is a mechanism in which gene expression depends upon parental origin. Imprinted genes occur in regions of chromosomes with allele-specific differences in transcription and methylation.. Mutations can alter normal imprinting, thus causing genetic abnormalities. Prader-Willi Syndrome (PWS) and Angelman Syndrome (AS) are two ideal examples of imprinting. Both result from either a maternal or paternal deletion on chromosome 15 or from uniparental disomy, inheritence of both chromosomes of a pair from one parent. The expression of these syndromes is determined by parental origin of genes on chromosome 15. 70% of all patients have the deletion. Only paternal deletions occur in PWS and only maternal deletions in AS. In PWS both copies of chromosome 15 are inherited soley from the mother and none from the father; the situation is reversed in AS.
Each disorder has a distinct phenotype. PWS, a neurobehavioral disorder affecting 1 in 10,000 newborns, has dysmorphic features that vary throughout childhood, adolescence and adulthood. These include hypotonia and poor sucking reflex, hyperphagia leading to obesity, short stature and extremities, and moderate mental retardation. In contrast, AS features include hyperactivity, laughter outbursts, clumsy, jerky movements, large facial features, and severe mental retardation.
DNA methylation probes and RFLP analysis have been used extensively to determine the origin of these unusual anomalies. Karyotyping has revealed a translocation between chromosomes 6 and 15 and high-resolution banding techniques showed a partial deletion of the 15q11q13 region of chomosome 15. The SNRPN gene has been mapped to chromosome 15 and encodes the small polypeptide N (SmN). SmN is part of the SnRNP's which catalyze mRNA splicing. PWS patients with a chromosomal deletion were also found to be missing a copy of SNRPN. This mutation disrupts the pattern of methylation at adjacent gene loci, which can alter gene interactions and lead to abnormal imprinting.
Uniparental disomy occurs when both chromosomes of a pair are inherited from one parent. In PWS two copies of chromosome 15 are inherited from the mother, whereas, in AS two copies are inherited from the father. This contradicts Mendel's laws of chromosome pairing and segregation: chromosome pairing should result in three phenotypes of homozygous dominent, homozygous recessive or heterozygous. As a consequence of translocation, nondisjunction in meiosis I causes an unequal splitting of chromosome 15, yielding a zygote with either two copies or no copies of the chromosome. Meiosis I may also result in the loss of a chromosome. Since the frequency of trisomy in chromosome 15 is high, a maternal loss of a chromosome by meiotic nondisjunction would lead to a normal zygote. However, a random loss in the paternal chromosome would lead to PWS. Studies have also linked age to frequency of maternal uniparental disomy: with advanced age comes greater probability of nondisjunction events.
PWS and AS are unusual, frightening disorders. Deletions, random loss of chromosomes, and nondisjunction play major roles in determining their phenotypes, and are helpful in diagnosis and genetic counseling. Imprinting genes with allele-specific differences in transcription and methylation can be altered by deletions and uniparental disomy leading to PWS and AS. These and other disorders can benefit from extensive studies into genomic imprinting.


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