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Relaxation of imprinting in Prader-Willi syndrome
P K Rogan1, J R Seip, L M White
1Department of Human Genetics, MCP-Hahnemann School of Medicine, Pittsburgh, PA 15212, USA. progan@pgh.allegheny.edu
Insights
Two Prader-Willi syndrome (PWS) patients with maternal uniparental disomy (UPD) showed atypical gene expression and DNA replication patterns. This relaxed imprinting correlated with their milder PWS phenotypes.
Area of Science:
- Genetics
- Molecular Biology
- Developmental Biology
Background:
- Prader-Willi syndrome (PWS) is a complex genetic disorder typically caused by the loss of function of imprinted genes on chromosome 15.
- Maternal uniparental disomy (UPD) of chromosome 15, where both copies of chromosome 15 are inherited from the mother, is one known cause of PWS.
Observation:
- Two PWS patients with maternal UPD exhibited atypical growth and development, with absent hyperphagia and polyphagia.
- Analysis of multiple genomic loci revealed unusual patterns of gene expression and DNA replication compared to typical PWS cases.
Findings:
- While the SNRPN gene maintained maternal imprinting, other imprinted genes (PAR5, ZNF127, IPW) showed variable expression in the patients.
- Asynchronous DNA replication was observed across most analyzed loci, except for SNRPN, suggesting a coordinated disruption of imprinting.
- These findings indicate that a subset of imprinted genes can be transcribed in some PWS patients with maternal UPD.
Implications:
- Relaxed imprinting, characterized by altered gene expression and asynchronous replication, may contribute to the milder clinical phenotypes observed in these PWS patients.
- Understanding these molecular variations is crucial for refining PWS diagnostics and exploring genotype-phenotype correlations.
- This study highlights the complexity of genomic imprinting and its role in human development and disease.
Abstract:
We describe two Prader-Willi syndrome (PWS) patients who exhibit maternal uniparental disomy (UPD) of chromosome 15 and unusual patterns of gene expression and DNA replication. Both were diagnosed during infancy as having PWS; however, their growth and development were atypical compared with others with this condition. Weight was below normal in the first patient, and height and development were within normal limits in the second individual. Hyperphagia and polyphagia were not evident in either patient. Genotypes at multiple genomic loci, allele-specific methylation, gene expression, and DNA replication were analyzed at D15S9 [ZNF127], D15S63 [PW71], SNRPN, PAR5, IPW, and D15S10 in these patients. The maternal imprint (based on the absence of gene expression, synchronous replication, and methylation of both alleles) was retained at SNRPN in these patients, as is the case in others with UPD. By contrast, cells from the first individual expressed PAR5 and ZNF127, whereas the second expressed a single IPW allele. Asynchronous DNA replication was observed in both patients at all loci, except SNRPN. These findings show that a subset of imprinted genes can be transcribed in some PWS patients with maternal UPD and that asynchronous DNA replication is coordinated with this pattern of gene expression. Relaxed imprinting in these patients is consistent with their milder phenotype.