Disruption of the mouse necdin gene results in early post-natal lethality

Prader-Willi syndrome (PWS) is a neurobehavioural disorder characterized by neonatal respiratory depression, hypotonia and failure to thrive in infanc y, followed by hyperphagia and obesity among other symptoms(1,2). PWS is ca used by the loss of one or more paternally expressed genes on chromosome 15 q11-q13, which can be due to gene deletions, maternal uniparental disomy or mutations disrupting the imprinting mechanism. Imprinted genes mapped to t his region include SNRPN (refs 3,4), ZNF127 (ref. 5), IPW (ref. 6) and NDN (which encodes the DNA-binding protein necdin; refs 7-10). The mouse homolo gues of these genes map to mouse chromosome 7 in a region syntenic with hum an 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 wa s isolated in the mouse Snrpn genomic region which, when deleted on the pat ernally inherited chromosome, resulted in the loss of expression of all fou r genes and early post-natal lethality(13). To determine the possible contr ibution of Ndn to the PWS phenotype, we generated Ndn mutant mice. Heterozy gous mice inheriting the mutated maternal allele were indistinguishable fro m their wild-type littermates. Mice carrying a paternally inherited Ndn del etion allele demonstrated early post-natal lethality. This is the first exa mple of a single gene being responsible for phenotypes associated with PWS.