Box 16.6Molecular pathology of Prader-Willi and Angelman syndromes

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are both caused by problems with differentially imprinted genes at 15q11-q13. They exemplify the complicated molecular pathology associated with clusters of imprinted genes.

  • PWS (MIM 176260: mental retardation, hypotonia, gross obesity, male hypogenitalism) is caused by loss of function of genes that are expressed only from the paternal chromosome.
  • AS (MIM 105830: mental retardation, lack of speech, growth retardation, hyperactivity, inappropriate laughter) is due to loss of function of a closely linked gene that is expressed only from the maternal chromosome. Some children with AS will have two functional copies of the PWS genes, and vice versa, but this over-expression does not appear to have any phenotypic effect.

As shown in the Table, a variety of events can lead to lack of a paternal (PWS) or a maternal (AS) copy of the relevant chromosome 15 sequences.

  • De novo deletions of 15q11-q13 are the commonest cause. Usually the deletions are large and remove the same sequences in both PWS and AS; rare cases with small deletions show that the PWS and AS critical regions are adjacent but not overlapping.
  • Uniparental disomy is detected when DNA marker studies show that a person with apparently normal chromosomes has inherited both homologs of a particular pair (No. 15 in this case) from one parent. The usual cause is trisomy rescue. A trisomy 15 conceptus develops to a multicell stage; normally it would die, but if a chance mitotic nondisjunction (Section 2.6.2) produces a cell with only two copies of chromosome 15 at a sufficiently early stage of development, that cell can go on to make the whole of a surviving baby. Most trisomy 15 conceptuses are 15M15M15P. One time out of three, random loss of one chromosome 15 will produce a fetus with maternal uniparental disomy, 15M15M. Lacking any paternal 15, the fetus will have Prader-Willi syndrome.
  • AS may be caused entirely by lack of expression of the UBE3A gene, since some inherited cases have apparently normal chromosome structure and imprinting, but have point mutations in this gene. The cause of PWS may be more complex, because no simply inherited cases have been found.
  • Occasionally something has gone wrong with the mechanism of imprinting. Both chromosome 15 homologs carry the same parent-specific methylation pattern, although marker studies show they originate from different parents. Such cases are very interesting for the light they throw on the imprinting mechanism.

Origins of Prader-Willi and Angelman syndromes

Origins of Prader-Willi and Angelman syndromes

EventProportion of PWSProportion of AS
Uniparental disomy~20%~3%
Point mutationsnot seen~15% (in UBE3A gene)
Imprinting errors~2%~5%

From: Chapter 16, Molecular pathology

Cover of Human Molecular Genetics
Human Molecular Genetics. 2nd edition.
Strachan T, Read AP.
New York: Wiley-Liss; 1999.
Copyright © 1999, Garland Science.

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