The role of ancient gene variants in Prader-Willi syndrome pathophysiology

Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder caused by genetic defects within a locus on chromosome 15(15q11-q13), in which the loss of expression of paternally inherited genes causes severe symptoms; for example, neurodevelopmental delays, hyperphagia, and obesity, as well as various disturbances in the rhythms of sleep and wakefulness. This parent-of-origin genetic mechanism, namely genomic imprinting, emerged during the evolution of placental mammals and accumulated pivotal functions in organismal homeostasis, metabolism, and sleep-wake behaviours.

Recently we have identified an appealing evolutionary mechanism involved in the nuclear pore functions, which promises to reveal an understanding of how the cellular mechanisms related to the obesity in PWS are regulated. In particular, our preliminary data suggest a cross-link between the lipid homeostasis of PWS patients and their circadian alteration. 3D modelling of ancient variants of a PWS gene, namely NPAP1, predicted that the structure of its protein is a determinant for altered dynamics in lipid accumulation and circadian homeostasis.

The results of our investigation will lead to a better comprehension of why PWS patients, which are lean in infancy due to feeding difficulties, later develop obesity and sleep-wake disturbances. Finally, by developing new genetic drugs that we will test in our PWS experimental models, we will advance a novel therapy for PWS patients.