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
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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3. Nichols, Robert. D.; Knoll, Joan HM.; Butler, Merlin g.; Karam, Susan;
Lalande, Marc. Genetic Imprinting Suggested by Maternal Heterodisomy in
Nondeletion PWS. Nature: vol 342; Nov 1989; 281-285.
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