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Genomic Imprinting
Definition:
Genomic imprinting is an epigenetic phenomenon in which expression of a gene depends on its parent of origin. Although an individual inherits two alleles of an autosomal gene, one allele, maternal or paternal, is selectively transcriptionally silenced.
Genomic imprinting is an epigenetic phenomenon in which expression of a gene depends on its parent of origin. Although an individual inherits two alleles of an autosomal gene, one allele, maternal or paternal, is selectively transcriptionally silenced.
- Maternal imprinting: maternal allele is silenced, so paternal allele is expressed.
- Paternal imprinting: paternal allele is silenced, so maternal allele is expressed.
This differs from classical Mendelian inheritance because the phenotype depends on whether the defective allele came from the mother or father.
Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 174.
Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 174.
Mechanism
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Establishment of imprint
- Imprinting is established in the germ cells, in the ovum or sperm, before fertilization.
- The imprints are erased and reset during germ-cell development according to the sex of the individual producing the gamete.
-
Epigenetic silencing
- It is mainly mediated by differential DNA methylation at CpG nucleotides.
- Imprinted genes are commonly arranged in clusters regulated by cis-acting imprinting control regions.
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Maintenance
- After fertilization, the parental imprinting pattern is stably maintained in somatic cells through mitosis.
- Therefore, for an imprinted locus, only one parental allele is functionally active.
About 200 to 600 human genes are estimated to be imprinted.
Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 174.
Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 174.
Clinical significance: chromosome 15 imprinting disorders
The classical examples are Prader-Willi syndrome (PWS) and Angelman syndrome (AS). Both involve the chromosome 15q11.2-q13 region, but differ according to the parent from whom the affected chromosome is inherited.
| Feature | Prader-Willi syndrome | Angelman syndrome |
|---|---|---|
| Lost functional contribution | Paternal genes | Maternal UBE3A gene |
| Usual deletion | Paternal 15q11.2-q13 deletion | Maternal 15q11.2-q13 deletion |
| Principal clinical features | Hypotonia, intellectual disability, hyperphagia, obesity, short stature, small hands and feet, hypogonadism | Intellectual disability, microcephaly, seizures, ataxic gait, inappropriate/excessive laughter |
| Parent-of-origin principle | Maternal genes in PWS region are normally imprinted and silent | Paternal UBE3A is imprinted and silent in relevant brain regions |
1. Prader-Willi syndrome
In the PWS region, several genes on the maternal chromosome 15 are normally imprinted and silenced. Thus, expression normally depends on the paternal copy.
Loss of paternal gene expression causes PWS by:
- Paternal deletion of 15q11.2-q13, the commonest mechanism
- Maternal uniparental disomy, where both chromosome 15 copies are maternal
- Imprinting defect, where the paternal chromosome carries a maternal-type imprint
No single gene accounts for all manifestations of PWS; multiple paternally expressed genes, including small nucleolar RNA-related genes, are implicated.
2. Angelman syndrome
Angelman syndrome occurs when there is loss of the active maternal UBE3A allele.
- In the brain, UBE3A is predominantly expressed from the maternal chromosome because the paternal copy is imprinted.
- UBE3A encodes a ubiquitin ligase involved in protein ubiquitination.
- Its deficiency impairs synapse formation and synaptic plasticity.
Causes include:
- Maternal deletion of 15q11.2-q13
- Paternal uniparental disomy
- Defective imprinting of the maternal chromosome
- Pathogenic mutation of maternal UBE3A
Mechanisms producing imprinting disorders
-
Deletion
Deletion of the only active allele causes disease.- Paternal deletion: PWS
- Maternal deletion: Angelman syndrome
-
Uniparental disomy
Both homologues of a chromosome are inherited from one parent.- Two maternal chromosome 15 copies: PWS
- Two paternal chromosome 15 copies: Angelman syndrome
-
Imprinting defects
The chromosome has an inappropriate parental methylation pattern.- Paternal chromosome with maternal imprint: PWS
- Maternal chromosome with paternal imprint: Angelman syndrome
Conclusion
Genomic imprinting is parent-specific, epigenetic gene silencing, chiefly mediated by DNA methylation. It explains how identical chromosomal deletions may produce different syndromes depending on parental origin, as demonstrated by Prader-Willi and Angelman syndromes.
Robbins, Cotran & Kumar Pathologic Basis of Disease, pp. 174-175.
Robbins, Cotran & Kumar Pathologic Basis of Disease, pp. 174-175.
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