Trends in Genetics
Volume 14, Issue 5, 1 May 1998, Pages 194-200
Journal home page for Trends in Genetics

Imprinting in Prader–Willi and Angelman syndromes

https://doi.org/10.1016/S0168-9525(98)01432-2Get rights and content

Abstract

Imprinted genes are marked in the germline and retain molecular memory of their parental origin, resulting in allelic expression differences during development. Abnormalities in imprinted inheritance occur in several genetic diseases and cancer, and are exemplified by the diverse genetic defects involving chromosome 15q11–q13 in Prader–Willi (PWS) and Angelman (AS) syndromes. PWS involves loss of function of multiple paternally expressed genes, while mutations in a single gene, UBE3A, which is subject to spatially restricted imprinting, occur in some AS patients. Identification of mutations in the imprinting process in PWS and AS has led to a definition of an imprinting center (IC), involving the promoter (in PWS) or an alternative transcript of the SNRPN gene (in AS). The IC regulates initiation of imprint switching for all genes in a 2 Mb imprinted domain during gametogenesis. Imprinting mutations define a novel mechanism of genetic disease because they have no direct effect in the affected patient but, rather, it is the parental germline effect of an IC mutation that leads to disease in the offspring.

Section snippets

Molecular classes of PWS and AS

There are multiple genetic mechanisms that can lead to PWS and AS, but despite this complexity each leads to a common gene deficit[3]. Each molecular mechanism in PWS and AS abolishes imprinted (parent-of-origin-specific) expression, such that paternal gene expression is silenced in PWS, and maternal gene expression is abolished in AS (Fig. 2). The most common genetic mechanism in PWS and AS is a large chromosomal deletion that is the same size in the majority of deletions in these syndromes3, 7

The AS gene (UBE3A) encodes a ubiquitin-protein ligase

The location of the AS gene was initially narrowed down by the study of rare patients with atypical deletions[3]and the identification of an inversion breakpoint within a candidate gene[18]. This was the previously characterized UBE3A gene, which has been shown to have mutations in four AS patients, including familial cases18, 19. These include a de novo 5 bp duplication and a maternally inherited splice mutation, both leading to frameshifts and premature translation termination[18], as well as

Candidate genes for PWS

Chromosome 15q11–q13 has three subregions (Fig. 3a), including a distal non-imprinted region, a central region containing a gene expressed from the maternally inherited chromosome only, involved in AS, and a proximal region containing paternal-only expressed genes, at least some of which are involved in PWS. At least seven genes and ESTs expressed from the paternal chromosome only have been identified in 15q11–q13 (Refs 3, 11, 31, 32, 33, 34; Fig. 3a) (M.T.C. Jong et al., unpublished; T.C.

Imprinting mutations in PWS and AS

During the life cycle, imprinting must switch at each generation and be reset in developing germ cells, so that the maternal or paternal imprint is specific for the sex of the individual. Perhaps one of the most remarkable findings to come from study of PWS and AS is that of patients with mutations in this imprint-switch process. This is critical not only for a molecular understanding of imprinting in 15q11–q13, but potentially for other imprinted chromosomal regions because similar mutations

The imprinting center and mechanisms of imprinting

Because all imprinted genes studied have been associated with differential DNA methylation (see Fig. 3b), models have been invoked in which DNA methylation is the key or only regulator of imprinting. Inherent in such models is the idea that DNA methylation represents the gametic mark that is inherited, and imparts the maternal- or paternal-specific allelic information to cells of the embryo and adult3, 31, 36, 37. DNA-methyltransferase-deficient mice have been produced that have loss of

Evolutionary conservation of imprinting

Genes from human chromosome 15q11–q13 have homologs in mouse chromosome 7C (Refs 3, 34, 53, 54, 55, 56, 57; M.T.C. Jong et al., unpublished) (Fig. 5). Genetic breeding of chromosome rearrangements has led to animals with maternal or paternal UPD for the central region of chromosome 7 (Fig. 5), which have an imprinted phenotype53, 57. The maternal UPD is a genetic model of PWS, but the animals die postnatally before weaning[53]. This might be a consequence of hypotonia and failure to thrive, as

The molecular life cycle of imprinting

The mechanism by which imprinting is set in the germline, maintained in embryogenesis and postnatal development, and reversed in the germline, is largely unknown. However, based on the descriptions above of gene-specific DNA-methylation imprints and of an IC involved in germline switching of the imprint over a 2 Mb imprinted domain, we can formulate a model for the regulation of imprinting in 15q11–q13 throughout the mammalian life-cycle. The primary step in initiation of imprint switching in

Acknowledgements

We apologize to authors whose work could not be cited because of space limitations. We thank T.A. Gray and J.M. Gabriel for critical comments on the manuscript, and members of our laboratories for their contributions to our research. Supported by the National Institutes of Health (HD31491) to R.D.N., the Human Frontiers of Science Program (R.D.N., B.H.), the American Cancer Society (DDC-86521 to R.D.N.), and the Deutsche Forschungsgemeinschaft (B.H.).

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