X-inactivation, Imprinting, and Uniparental Disomy

According to traditional Mendelian principles, the parental origin of a mutant gene is irrelevant for the expression of the phenotype. There are, however, important exceptions to this rule.

 X-inactivation prevents the expression of most genes on one of the two X-chromosomes in every cell of a female.
Gene inactivation also occurs on selected chromosomal regions of autosomes. This phenomenon, referred to as genomic imprinting, leads to inheritable preferential expression of one of the parental alleles. It is of pathophysiologic importance in disorders where the transmission of disease is dependent on the sex of the transmitting parent and, thus, plays an important role in the expression of certain genetic disorders. Two classic examples are the Prader-Willi syndrome and Angelman syndrome .

Prader-Willi syndrome is characterized by diminished fetal activity, obesity, hypotonia, mental retardation, short stature, and hypogonadotropic hypogonadism. Deletions of the paternal copy of the Prader-Willi locus located on the short arm of chromosome 15 result in a contiguous gene syndrome involving missing paternal copies of the necdin and SNRPN genes, among others. In contrast, patients with Angelman syndrome, characterized by mental retardation, seizures, ataxia, and hypotonia, have deletions involving the maternal copy of this region on chromosome 15. These two syndromes may also result from uniparental disomy. In this case, the syndromes are not caused by deletions on chromosome 15 but by the inheritance of either two maternal chromosomes (Prader-Willi syndrome) or two paternal chromosomes (Angelman syndrome).

Genomic imprinting, or uniparental disomy, is involved in the pathogenesis of several other disorders and malignancies. For example, hydatidiform moles contain a normal number of diploid chromosomes, but they are all of paternal origin. The opposite situation occurs in ovarian teratomata, with 46 chromosomes of maternal origin.

Expression of the imprinted gene for insulin-like growth factor II (IGF-II) is involved in the pathogenesis of the cancer-predisposing Beckwith-Wiedemann syndrome (BWS). These children show somatic overgrowth with organomegalies and hemihypertrophy, and they have an increased risk of embryonal malignancies such as Wilm's tumor. Normally, only the paternally derived copy of the IGF-II gene is active and the maternal copy is inactive. Imprinting of the IGF-II gene is regulated by H19, which encodes an RNA transcript that is not translated into protein. Disruption or lack of H19 methylation leads to a relaxation of IGF-II imprinting and expression of both alleles.

Meiotically and mitotically heritable changes in gene expression not associated with DNA sequence alterations are referred to as epigenetic effects. These changes involve DNA methylation, histone modifications, and RNA-mediated silencing, resulting in gene repression without a change in the coding sequence. Epigenetic alterations are increasingly recognized to play a role in human diseases such as cancer, mental retardation, hematologic disorders, and possibly in aging. For example, de novo methylation of CpG islands, regions of >500 bp in size with a GC content >55% in promoter regions that are normally unmethylated, is a hallmark of human cancers. Inhibitors of enzymes controlling epigenetic modifications such as histone deacetylases and DNA methyltransferases reverse gene silencing and represent a promising new group of antineoplastic agents.