Imprinting and Genetic Disease: Angelman, Prader-Willi, and Beckwith-Wiedemann Syndromes

Introduction to Genetic Imprinting

• Humans inherit two copies of each gene, one from each parent.
• Genetic imprinting involves one gene being epigenetically "turned off" or imprinted, affecting gene regulation rather than base sequence.
• Epigenetic mechanisms can lead to diseases when imprinted genes are defective or missing.

Mechanisms of Epigenetic Imprinting

• Involves methylation of DNA, which can silence gene expression.
• Occurs during the formation of egg or sperm cells.
• Linked to several genetic disorders, including Angelman syndrome, Prader-Willi syndrome, and Beckwith-Wiedemann syndrome.

Angelman Syndrome

• Characterized by developmental disabilities, seizures, speech deficits, and motor oddities.
• Prevalence: 1 in 15,000 to 20,000 globally.
• Caused by a deletion on chromosome 15 affecting the UBE3A gene, normally expressed from the maternal gene while the paternal gene is imprinted.
• Loss of maternal UBE3A leads to symptoms since the paternal copy is silenced.
• Uniparental disomy (two paternal copies) can also cause the syndrome.

Genetic Mechanisms for Angelman Syndrome

• A large deletion, mutation, or imprinting defect in the maternal UBE3A gene.
• In some cases, two paternal copies replace the maternal one, resulting in the disorder.

Prader-Willi Syndrome

• Caused by loss of paternal genes in the same chromosome 15 region as Angelman syndrome.
• Symptoms include hyperphagia, developmental delays, and decreased muscle tone.
• Involves loss of genes like SNRPN, important for mRNA splicing.

Beckwith-Wiedemann Syndrome

• Characterized by large birth size and tumor predisposition.
• Linked to loss of imprinting on chromosome 11 (region 11p15.5).
• Often involves uniparental paternal disomy.
• Genes such as H19 and Igf2 are involved.
• Loss of tumor suppressor gene expression and overexpression of oncogenes contribute to tumor risk.

Genetic Studies and Family Pedigrees

• Studies highlighted paternal imprinting through family pedigree analyses.
• Cases demonstrated a pattern where unaffected males passed the trait to grandchildren through daughters.

Conclusion

• Imprinting disorders result from epigenetic errors affecting gene expression.
• Research continues to understand these mechanisms for better diagnosis and treatment of associated disorders.

References

• Angelman, H. "Puppet" children: A report of three cases.
• Henry, I., et al. Uniparental paternal disomy in a genetic cancer-predisposing syndrome.
• Magenis, R. E., et al. Is Angelman syndrome an alternate result of del(15)(q11q13)?
• Viljoen, D., & Ramesar, R. Evidence for paternal imprinting in familial Beckwith-Wiedemann syndrome.