All humans inherit two copies of each gene (except, of course, the sex chromosome genes in males), carried on homologous maternal and paternal chromosomes. It was long assumed that there was no difference between normal homologous genes derived from the mother and the father. Indeed, this is true for most genes. It has been established, however, that functional differences exist between the paternal and the maternal copies of some genes. The differences arise from an epigenetic process called genomic imprinting, whereby certain homologous genes are differentially “inactivated” during paternal and maternal
Fig. 7.19 Sitesofexpansionandtheaffectedsequenceinselecteddiseasescausedbynucleotiderepeatmutations.UTR, Untranslatedregion.*Althoughnotstrictlyatrinucleotide-repeatdisease,progressivemyoclonusepilepsyiscaused,likeothersinthisgroup,byaheritableDNAexpansion.Theexpandedsegmentisinthepromoterregionofthegene.
http://ebooksmedicine.net gametogenesis. Thus, maternal imprinting refers to transcriptional silencing of the maternal allele, whereas paternal imprinting implies that the paternal allele is inactivated. At the molecular level, imprinting is associated with methylation of the gene promoter, as well as related events such as modification of DNA-binding histone proteins, the sum total effect of which is to silence the gene. Imprinting occurs in ova or sperm and is then stably transmitted to all somatic cells derived from the zygote.
Genomic imprinting is best illustrated by considering two uncommon genetic disorders, Prader-Willi syndrome and Angelman syndrome.
Mental retardation, short stature, hypotonia, obesity, small hands and feet, and hypogonadism characterize Prader-Willi syndrome. In 60% to 75% of cases, an interstitial deletion of band q12 in the long arm of chromosome 15—del(15)(q11;q13)—can be detected. In many patients without a detectable cytogenetic abnormality, FISH analysis shows smaller deletions within the same region. It is striking that in all cases, the deletion affects the paternally derived chromosome 15. In contrast to Prader-Willi syndrome, patients with the phenotypically distinct Angelman syndrome are born with a deletion of the same chromosomal region derived from their mothers. Patients with Angelman syndrome also are mentally retarded, but in addition they present with ataxic gait, seizures, and inappropriate laughter. Because of the laughter and ataxia, this syndrome has been called the happy puppet syndrome. A comparison of these two syndromes clearly demonstrates the “parent-oforigin” effects on gene function. If all the paternal and maternal genes contained within chromosome 15 were expressed in an identical fashion, clinical features resulting from these deletions would be expected to be identical regardless of the parental origin of chromosome 15.
The molecular basis of these two syndromes can be understood in the context of imprinting (