Genomic imprinting explains why deletion of the same chromosomal region (15q11-q13) causes two entirely different syndromes. Prader-Willi syndrome results from loss of the PATERNAL copy, while Angelman syndrome results from loss of the MATERNAL copy. Which molecular mechanism is most directly responsible for this parent-of-origin effect?

• A Trinucleotide repeat expansion on one parental chromosome causing anticipation
• B Differential DNA methylation of imprinting control regions that silences genes on one parental chromosome ✓
• C Uniparental disomy causing identical gene dosage from both parental chromosomes
• D X-inactivation spreading to the autosome 15 from the inactivated X chromosome

Explanation

Genomic imprinting is epigenetically controlled by differential DNA methylation of imprinting control regions (ICRs), established during gametogenesis and maintained after fertilization. In the 15q11-q13 region, the paternal copy expresses SNRPN and snoRNA genes (silenced maternally by methylation), while the maternal copy expresses UBE3A (silenced paternally). Loss of the paternal chromosome 15 in Prader-Willi removes active SNRPN; loss of the maternal chromosome 15 in Angelman removes active UBE3A (which encodes ubiquitin-protein ligase E3A essential for neuronal function). Uniparental disomy of chromosome 15 achieves the same clinical effect by different mechanism.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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Written and medically reviewed by the StethoPrep medical team.