Voor het Angelman Syndroom

Research Dr. Buiting


ROTTERDAM - The summary of the presentation of Dr. Karin Buiting (Germany) called "Imprinting defects in Angelman syndrome" is available.

The chromosomal region 15q11q13 is subject to genomic imprinting and contains genes which are active only on the paternal chromosome and one gene, UBE3A, which is active only on the maternal chromosome.  As known, the loss of function of UBE3A leads to Angelman Syndrome (AS), whereas loss of function of paternally expressed genes leads to Prader-Willi syndrome (PWS).

Four major molecular mechanisms are known to cause Angelman syndrome:

  • Deletion (70% of the cases). In this case a part of the maternal chromosome 15 is missing
  • Paternal uniparental disomy (2% of the cases). In this situation  the patients have two paternal chromosomes 15 (instead of one maternal and one paternal chromosome 15)
  • Imprinting defect (3% of the cases). In this situation the patient has a maternal and paternal chromosome 15 but (epi)genetically the maternal chromosome 15 behaves as a paternal one (maternal chromosome has adapted a paternal epigenotype).
  • UBE3A mutation (5 to 10% of the cases)

All these molecular defects lead to a loss of function of UBE3A and therefore to Angelman syndrome. Furthermore, in a number of patients a clinical diagnosis of Angelman syndrome has been established but the molecular defect is unknown (10 to 20% of the cases).

After this introduction, the way genomic imprinting works, was presented.

Genomic imprinting is an epigenetic process that involves DNA methylation in order to modify the activation of genes from one parental copy only (maternal or paternal) without altering the DNA sequence. These epigenetic marks are erased and newly established in the germ line and are maintained throughout all somatic cells of an individual. Errors affecting this process lead to an imprinting defect.

To classify imprinting defects further, the following questions have to be answered:

  • When do imprinting defects occur?
  • Why do imprinting defects occur? Are there yet unknown DNA mutations in other genes involved?
  • Is the imprinting defect restricted to the disease specific locus or are there other imprinted loci affected as well?

At the study Dr. Buiting conducted in Essen (Germany) a number of 174 patients with imprinting defects participated. In nine of these patients the imprinting defect was due to a small deletion affecting the imprinting center. Such a deletion is associated with a 50% recurrence risk when the deletion is a familial mutation. In the majority (164) of patients it could be shown that the imprinting defect is a epimutation without changes in the DNA sequence caused either by a failure to establish the imprint in the female germline or by a problem to maintain the imprint in early development. The latter defect results in a mosaic situation, which means that patients have normal cells and cells with an imprinting defect. In more than 50% of the patients, somatic mosaicism was detected. This was surprising higher than expected. Methylation mosaic can be detected by methylation analysis.  To obtain highly quantitative DNA methylation patterns, Dr. Buiting and her colleagues established high resolution methylation analysis using next generation bisulfite sequencing on the Roche/454 Genome Sequencing junior system. This allows determining the degree of the methylation mosaic more exactly and may help to find out if mosaic patients are less severely affected than other patients.

Conclusions of this part of the research are:

  • It seems that patients with an Imprinting Defect (ID) tend to be less severely affected than patients with a common large deletion.
  • Furthermore, patients with a mosaic ID can have an even milder or an atypical phenotype.
  • Some of them have overlapping features with PWS.

In the current research project Dr. Buiting and her colleagues focus on the identification of mutations or variations in genes which are involved in regulation of imprinting and if a subgroup of AS patients have multiple methylation defects as known from other imprinting diseases. So far, they found no evidence for genetic variants  which modify the risk for imprinting defects in AS by genome wide gene dosage and single nucleotide polymorphism (SNP) analyses performed in 62 patients with AS and an ID. It is planned to extend this study in the next research period using improved techniques such as high throughput sequence analysis.

Are there multiple imprinting defects in patients with PWS-ID or AS-ID?
Dr. Buiting ended her presentation with the following observation that will have to be investigated further in the next research period: From the first results obtained it looks that in Prader Willy Syndrome and Angelman Syndrome the imprinting defects seem to be restricted to chromosome 15, whereas in other imprinting disorders (Transient diabetes mellitus, Beckwith-Wiedeman syndrome and Silver-Russell syndrome) multiple imprinting defects occur in a restricted number of patients. This raises the question: „Is there any difference between imprinting defects where fetal and postnatal growth is affected and imprinting defects with a neurogenetic defect?“

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