Abstract
Prader-Willi syndrome (PWS) is a neurobehavioural disorder characterized by neonatal respiratory depression, hypotonia and failure to thrive in infancy, followed by hyperphagia and obesity among other symptoms1,2. PWS is caused by the loss of one or more paternally expressed genes on chromosome 15q11–q13, which can be due to gene deletions, maternal uniparental disomy or mutations disrupting the imprinting mechanism. Imprinted genes mapped to this region include SNRPN (refs 3 ,4), ZNF127 ( ref. 5), IPW (ref. 6) and NDN (which encodes the DNA-binding protein necdin; refs 7,8,9,10). The mouse homologues of these genes map to mouse chromosome 7 in a region syntenic with human chromosome 15q11–q13 (refs 7,11). Imprinting of the human genes is under the control of an imprinting center (IC), a long-range, cis-acting element located in the 5′ region of SNRPN (ref. 12). A related control element was isolated in the mouse Snrpn genomic region which, when deleted on the paternally inherited chromosome, resulted in the loss of expression of all four genes and early post-natal lethality13. To determine the possible contribution of Ndn to the PWS phenotype, we generated Ndn mutant mice. Heterozygous mice inheriting the mutated maternal allele were indistinguishable from their wild-type littermates. Mice carrying a paternally inherited Ndn deletion allele demonstrated early post-natal lethality. This is the first example of a single gene being responsible for phenotypes associated with PWS.
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Acknowledgements
We thank T. Shatzer and L. Sewel for animal care; T. Sullivan for technical assistance; K.U. Wagner for the Cre expressing mice; L. Tessarollo for mice and discussion; J. Ward for help in histopathology; A. Wang for reading the manuscript; and members of the lab for discussions. This research was sponsored by the National Cancer Institute, DHHS, under contract with ABL. R.W. was supported by the Medical Research Council of Canada and a Basil O'Connor Scholarship from the March of Dimes.
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Gérard, M., Hernandez, L., Wevrick, R. et al. Disruption of the mouse necdin gene results in early post-natal lethality . Nat Genet 23, 199–202 (1999). https://doi.org/10.1038/13828
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DOI: https://doi.org/10.1038/13828
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