A child with Angelman syndrome was found to have uniparental disomy (UPD) of chromosome 15 — both copies derived from the father. Why does paternal UPD of chromosome 15 cause Angelman syndrome rather than Prader-Willi syndrome?

• A The UBE3A gene (15q11-13) is maternally imprinted and expressed only from maternal allele; paternal UPD means no maternal UBE3A expression → Angelman syndrome ✓
• B The paternal copy of chromosome 15 carries the active UBE3A gene; paternal UPD gives two active copies preventing PWS
• C Paternal UPD 15 causes overexpression of SNRPN gene causing PWS — Angelman results from maternal deletion not paternal UPD
• D Both conditions result from paternal UPD; the phenotype depends on the specific breakpoint within 15q11-13

Explanation

Angelman syndrome results from loss of maternal UBE3A expression. UBE3A (E6-AP ubiquitin ligase) is subject to imprinting specifically in neurons — the paternal allele is silenced by a paternal-specific antisense transcript, so only the maternal allele is expressed in neurons. With paternal UPD (two paternal copies), neither allele can express UBE3A in neurons → Angelman syndrome. Conversely, maternal UPD (both maternal) causes PWS because it lacks expression of the paternally-imprinted SNRPN, NDN, and other genes in the 15q11-13 region. This is why UPD causes the 'opposite' syndrome from deletion of the same region.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.