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Towards a molecular understanding of Prader-Willi and Angelman syndromes
1Howard Hughes Medical Institute and Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Insights
Prader-Willi syndrome (PWS) and Angelman syndrome (AS) research advances understanding of imprinted gene expression on chromosome 15. New findings in human and mouse models reveal insights into these complex neurological disorders.
Area of Science:
- Genetics
- Neuroscience
- Epigenetics
Background:
- Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct neurological disorders.
- Both PWS and AS are linked to chromosome 15q11-q13 and involve imprinted gene expression.
- PWS results from deficient paternal gene expression, while AS stems from deficient maternal gene expression.
Purpose of the Study:
- To investigate the molecular basis of PWS and AS.
- To identify new transcripts and exons in the critical chromosomal region.
- To examine the epigenetic status and imprinting center function in human and mouse models.
Main Methods:
- Molecular analysis of human chromosome 15q11-q13 and mouse chromosome 7.
- Identification of novel transcripts and exons.
- Epigenetic status examination.
- Characterization of the imprinting center.
- Analysis of non-deletion Angelman syndrome patients.
Main Results:
- New transcripts and exons were identified in the PWS/AS region.
- Imprinting center function was conserved between mice and humans, demonstrated by a mouse model.
- UBE3A intragenic mutations were found in a significant number of non-deletion AS cases.
- Evidence suggests other genes may contribute to the AS phenotype.
Conclusions:
- Recent research has advanced the understanding of PWS and AS molecular mechanisms.
- Imprinted gene regulation in the PWS/AS region shows conservation across species.
- Further research is needed to fully elucidate the complexities of these syndromes.
Abstract:
Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are two distinct neurological disorders that map to human chromosome 15q11-q13 and involve perturbations of imprinted gene expression. PWS is caused by a deficiency of paternal gene expression and AS is caused by a deficiency of maternal gene expression. Experiments in the last year have focused on molecular analysis of the human chromosomal region as well as the homologous region on central mouse chromosome 7. New transcripts and exons have been identified and the epigenetic status of the PWS/AS region in mice and humans has been examined. The imprinting center that is hypothesized to control the switch between the maternal and paternal epigenotypes has also been characterized in greater detail and a mouse model that deletes the homologous element demonstrates a conservation in imprinting center function between mice and humans. In addition, analysis of non-deletion AS patients has revealed that UBE3A intragenic mutations are found in a significant number of cases. However, both human patients and mouse model systems indicate that other genes may also contribute to the AS phenotype. Thus, although much has been learned in the last year, considerable information is still required before these complex syndromes are fully understood.