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Imprinting and Angelman's syndrome

The revision of the conclusions of two recent reports of Angelman's syndrome' 2 by Professor Hall3 is correct in pointing out the consistency of the observations with those expected owing to genetic imprinting. However, the importance of the results is underrated even in this revision. The essential observation made was that the maternal transmission of pericentric inversions of chromosome 15 (inv(15)(pllql3)) resulted in offspring with Angelman's syndrome, while the mothers carrying the inversion were unaffected. Whereas the authors of the original reports postulated that the inversion 'unmasked' a recessive gene for the condition transmitted by the father, the role of imprinting in this parentally determined susceptibility was highlighted by Professor Hall,who predicted that the mothers would have to have inherited the rearrangement from their fathers to be unaffected. On first appraisal, this conclusion contradicts what is known about imprinting on chromosome 15, that the area deleted to yield Angelman's syndrome or Prader-Willi syndrome is identical, not only in cytogenetic (15ql 1-13)4 but also in molecular terms,5 dependent only on the parent of origin of the deleted chromosome (AS maternal, PWS paternal). If this were true, then the paternal inheritance of the rearrangement by the probands' mothers in these cases should have resulted in maternal Prader-Willi syndrome. The pathological effect of imprinting apparently results from the production of nullisomy at a locus when a genetic event removes a functioning allele, the homologue of which has been rendered inactive owing to the imprinting process.6 In the 15ql1-13 region, several (a minimum of two) such loci must exist, inactive alleles occurring on both paternal and maternal chromosomes, in order to produce the discrete phenotypes. The pericentric inversions should be interpreted in this light, while adhering to the assumption implicit in the previous assessments: that, as the mothers express the rearrangement in a non-mosaic manner in their somatic cells, they probably inherited the inversion. Firstly, if the inverted segment has led to incapacitation of the 15qll-13 region, and as it is being inferred that the individual loci giving rise to PraderWilli and Angelman's syndromes are distinct, it may be concluded that the locus (loci) for the former is located more distally, beyond the breakpoints in these cases. If there is indeed a submicroscopic deletion associated with the inversion, then the status of the rearranged segment is crucial. If the rearranged segment is not inactivated, which would be more consistent with viability, then the pathological consequences are mostly attributable to the deletion. In this case, the locus (loci) for Angelman's syndrome are within the deleted segment, and the Prader-Willi locus (loci) may be proximal or distal to this. Furthermore, the rearrangement could indeed be inherited from grandfathers. It is also possible that further genetic events have taken place in the Angelman patients. The final possibility is that the mothers do in fact have loci nullisomic owing to imprinting, but that the deletion is sufficiently small that compensatory mechanisms to prevent the development of Prader-Willi syndrome are effective. Whatever the molecular event, the main conclusion which may be drawn is that, apart from the last possibility, these cases confirm the independence of the Prader-Willi and Angelman loci, suggest that if multiple loci govern Angelman's syndrome they are within a relatively restricted stretch of DNA uninterrupted by Prader-Willi loci, and confirm the importance of imprinting in the region. In short, the loci for Prader-Wili and Angelman's syndromes may be distinguishable using the DNA of these patients, and the chromosomal status of the maternal grandparents must be ascertained, a point stressed by Professor Hall.