Genetic Imprinting in the Prader–Willi and Angelman Syndromes


Imprinted genes are expressed from only one of the two parental alleles: they are located in a few, specific chromosomal regions. The parental‐specific expression is obtained through epigenetic modifications (DNA methylation, histone tail modifications) which alter the conformation of chromatin fibre and therefore regulate the expression of the underlying genes. Deletions, duplications, mutations or imprinting defects of the only active allele, as well as uniparental disomy or loss of imprinting of the inactive allele lead to an unbalance (loss of function or gain of function) in the dosage of the gene product and do have phenotypic consequences. Two such examples in human pathology are represented by the Prader–Willi and Angelman syndromes, two phenotypically different conditions, whose phenotypes result from loss of paternal or maternal contribution of the 15q11–q13 genomic region, respectively.

Key Concepts:

  • Prader–Willi and Angelman syndromes are caused by loss of function of different genes located in a genomic region under the control of a single, bipartite imprinting centre.

  • These two condition represent the prototype of genomic imprinting disorders in humans.

  • Genomic imprinting regulates allelic expression according to the parental origin.

  • Imprinted genes are commonly expressed in half dosage.

  • Imprinted genes can be inactivated by different mechanisms: uniparental disomy, microdeletion, gene mutation, primary or secondary epigenetic mutation of the imprinting centre.

Keywords: imprinting; epimutation; Prader–Willi syndrome; Angelman syndrome

Figure 1.

Genomic imprinting: resetting, establishment and maintenance and possible imprinting defects. Erasure of imprinting occurs in primordial germ cells (actively on the maternal chromosome [pink] or by default on the paternal one [blue]); imprinting is reestablished in germ cells according to the male or female gonadic environment; the blue arrows indicate the specific stage and parental chromosome at which the error occurs. The phenotypic consequences (PWS or AS) of these errors are indicated. Adapted from Horsthemke .

Figure 2.

The PWS–AS imprinting domain. The imprinting centre (IC) has bipartite structure: PWS‐IC (empty circle) and AS‐IC (black circle). The majority of the genes in the cluster is reported. Those paternally expressed are in blue, whereas those maternally expressed are in pink. In black boxes the nonimprinted genes are shown. Adapted from Buiting .



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Further Reading

Katari S, Turan N, Bibikova M et al. (2009) DNA methylation and gene expression differences in children conceived in vitro or in vivo. Human Molecular Genetics 18: 3769–3778.

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Wawrzik M, Unmehopa UA, Swaab DF et al. (2010) The C15orf2 gene in the Prader–Willi syndrome region is subject to genomic imprinting and positive selection. Neurogenetics 11: 153–161.

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Gurrieri, Fiorella, and Sangiorgi, Eugenio(Nov 2011) Genetic Imprinting in the Prader–Willi and Angelman Syndromes. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0005532.pub2]