from DevBio or a companion website to Delopmental Biology by Scott Gilbert. The website no longer displays correctly in our browser, so is reproduced here.

The Genes Involved in Prader-Willi and Angelman Syndromes

In 1981, the Prader-Willi syndrome was found to be associated with a very small deletion in the long arm of human chromosome 15, between bands q11 and q13 (Ledbetter et al., 1981). However, in 1987, an identical deletion was reported in a number of patients who suffered from a very different disease, Angelman syndrome. These syndromes give quite distinct phenotypes (Figure 1). Prader-Willi syndrome is characterized by developmental delay, cryptorchidism (small or undescended testes), hyperphagia obesity (fatness due to overeating in an attempt to reach satiety), short stature, and mild retardation. Angelman syndrome is characterized by seizures, severe mental retardation, inappropriate laughter, and a characteristic face that is small with a large mouth and prominent chin.

Figure 1 Typical phenotypes of Angelman (left) and Prader-Willi (right) syndrome patients. The difference between them belies the fact they they are caused by the same chromosomal deletion. (From Nicholls, 1994; Photographs courtesy of R. D. Nicholls).

The resolution to the paradox of two different syndromes caused by the same chromosomal deletion came in 1989 when it was discovered the Prader-Willi syndrome was always caused by defects involving the paternally derived chromosome, while Angelman syndrome was always caused by deletions in the maternally derived chromosome (Knoll et al., 1989).

The deletion covers about 4 million base pairs and may involve several genes. Moreover, it appears that different genes may be responsible for the two syndromes, all of them being imprinted in the germline. The genes involved in Prader-Willi syndrome encode proteins that are only produced from the paternally derived chromosome. These include SNRPN, a gene which encodes the small ribonucleoprotein polypeptide SmN that is found in the fetal and adult brain, and ZFN127, a zinc-finger protein of unknown function. The hypopigmentation found in both syndromes is probably due to the loss of the P gene which is involved with pigment production. It is possible that the hypothalamic problems (such as overeating) associated with Prader-Willi syndrome might result from the loss of SNRPN. The production of this protein is found mainly in the hypothalamic regions of the brain and in the olfactory cortex. No candidate gene is known for the symptoms of the Angelman syndrome.

Recent research has shown that the Prader-Willi and Angelman syndromes are actually caused by different subdomains within this deleted region. Moreover, microdeletions of the 15q11-q13 region indicate that there is an "imprinting center" (IC). In chromosomes with these small deletions, the imprint is not changed when it passes through a new gamete, and the region retains the same imprint as it had when this deletion arose. These deletions all map to the same region. A map of the human 15q11-q13 region is shown in Figure 2.

Figure 2 Map of chromosome region 15q11-q13, showing regions causing Prader-Willi syndrome and Angelman syndrome as well as the maternal and paternal transcription patterns. Genes and genetic markers are shown as circles. The imprinting center is labeled. (After Saitoh et al., 1996).

This imprinting center is about 100 kilobases long and includes exon 1 of the SNRNP gene. Dittrich and colleagues (1996) have found novel transcripts originating from this region, representing alternatively spliced RNAs of the SNRPN transcript. Interestingly, these novel exons are only seen to be expressed form the paternal chromosome, and patients with Angelman or Prader-Willi syndromes have either deletions or mutations in this area. These mutations and deletions prevent the maternal to paternal imprinting switch in the Angelman Syndrome families and prevents the maternal to paternal switch in Prader-Willi families. Therefore, it is possible that the imprint center is needed to regulate alternative RNA splicing in the SNRPN gene transcripts.

The effects of imprinting can also be seen in those rare cases of Prader-Willi and Angelman Syndromes due to uniparental disomy for chromosome 15. In these cases, both copies of chromosome 15 come from either the male or the female. Uniparental disomy can occur during early development. Those people with both sets of chromosome 15 from their mothers have the absence of paternal genes in this region and develop Prader-Willi syndrome. Those people who have paternal uniparental disomy have Angelman Syndrome Nicholls, 1994). The methylation patterns in this region of chromosome 15 are consistent with the hypothesis that methylation may be the mechanism to distinguish the maternal and paternal genes (Driscoll et al., 1992; Mowery-Rushton et al., 1996; Glenn et al, 1996).
Literature Cited

Dittrich, B. and ten others. 1996. Imprint switching on human chromosome 15 may involve alternative transcripts of the SNRPN gene. Nature Genet. 14: 163-170.

Driscoll, D. J., Waters, M. F., Williams, C. A., Zori, R. T., Glenn, D. D., Avidano, K. M., and Nicholls, R. D. 1992. A DNA methylation imprint, determined by the sex of the parent, distinguishes the Angelman and Prader-Willi syndromes. Genomics 13: 917-924.

Glenn, C. C. and several others. 1996. Gene structure, DNA methylation, and imprinted expression of the human SNRNP gene. Amer. J. Human Genet. 58: 335-346.

Knoll. J. H. M., Nicholls, R. D., Magenis, R. E., Graham, J. M. Jr., Lalande, M., and Latt, S. A. 1989. Angelman and Prader-Willi syndromes share a common chromosome 15 deletion but differ in parental origin of the deletion. Amer. J. Med. Genet. 32: 285-290.

Ledbetter, D. H., Riccardi, V. M., Airhart, S. D., Strobel, R. J., Keenan, B. S., and Crawford, J. D. 1981. Deletion of chromosome 15 as a cause of Prader-Willi syndrome. New Engl. J. Med. 292: 63-66.

Mowery-Rushton, P.A., Driscoll, D. J., Nicholls, R. D., and Locker, J. 1996. DNA methylation patterns in human tissues of uniparental origin using a zinc-finger gene (ZNF127) from the Angelman/Prader -Willi region. Amer. J. Med. Genet. 61: 140-146.

Nicholls, R. D. 1994. Imprinting mechanisms and genes involved in Prader-Willi and Angelman syndromes. Semin. Devel. Biol. 5: 311-322.

Saitohm S. and several others. Minimal definition of the imprinting center and fixation of a chromosome 15q11-q13 epigenotype by imprinting mutations. Proc. Natl. Acad. Sci USA. In press.