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Npal3 – Immune deficiency in Prader-Willi?


The non-imprinted in Prader-Willi/Angelman syndrome (NIPA) genes encode for highly conserved receptor or transporter proteins and are involved in the development of the Prader-Willi Syndrome and the hereditary spastic paraplegia. The Prader-Willi Syndrome is a genetic disorder characterized by the failure to grow and gain weight during infancy, feeding problems, short stature, low muscle tone, and genital abnormalities. Between the ages of 6 months and 6 years infants may develop obesity. Affected individuals have characteristic facial features including almond-shaped eyes, a thin upper lip, and full cheeks. Additional abnormalities may include strabismus, small hands and feet, curvature of the spine, and mild to severe mental retardation.

Another protein family, the NIPA-like domain containing (NPAL) proteins, is closely related to the NIPA proteins, but to date nothing is known about their function. To elucidate the function of the Npal3 gene, knockout (Npal3 –/– ) mice were generated. Homozygous animals grew normal and were fertile without any obvious phenotype. However, intensive phenotypic analyses in the comprehensive primary phenotypic screen of the German Mouse Clinic revealed that disruption of the Npal3 gene results in a pleiotropic phenotype.


It was demonstrated earlier that changes in mRNA levels of NIPA1 and NIPA2 in Prader-Willi patients correlated with intellectual ability. The Npal3 gene encodes a protein with a similar structure compared to the NIPA proteins and also shows strong expression in the brain. Thus it could be expected that the disruption of the Npal3 gene might affect the behavior of Npal3 –/– mice. Analysis of mutant Npal3 females in the GMC behaviour screening demonstrated changes in social affinity, and mutant Npal3 males displayed deficits in exploratory behavior.

Surprisingly, the immunological screening revealed decreased numbers of natural killer cells (NK cells) in the mutants and higher concentrations of IgE in mutant males. Further changes in the levels of different immunoglobulines were observed.

The lung function screen demonstrated that again only male mutants were affected but females remained without any changes. In mutant males ventilation as well as specific tidal volumes and minute ventilation were significantly increased due to larger tidal volumes and elevated respiratory rates during rest and activity.

Alltogether, the Npal3 –/– mice could serve as a valuable model system for studying atopic diseases.


Targeted disruption of the mouse Npal3 gene leads to deficits in behaviour, increased IgE levels and impaired lung function“, Grzmil et al, Cytogenet Genome Res 2009, 125:186-200