Animal and cell models for Lesch-Nyhan syndrome

Abstract

Lesch–Nyhan Disease (LND) is a rare X-linked recessive metabolic and neurological syndrome due to the deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT). Peculiar neurological symptoms occur in LND: dystonia, choreoathetosis, compulsive self-injurious behaviour, with no obvious correlation to the deficiency of this purine salvage anzyme. A dopaminergic deficit was found to underlie the neurologic symptoms, but the aetiology for such alteration seemed inexplicable. Several lines of research were carried out to find the molecular basis for the neurological phenotype, and HPRT deficient animal and cellular models were developed. None of them, animal or cellular model, can be considered the completely proper one. Available animal models are rodents, which share several biochemical and molecular abnormalities with HPRT deficient patients, but do not display similar neurologic symptoms. Cellular models obtained from different cell lines present notable biochemical and molecular aberrations though many discrepancies suggest significant differences depending upon cell types and tissue source. Nevertheless, experimental studies on both models provided remarkable information on the biochemical and molecular pathways potentially responsible for the neurological damage in this disease, demonstrating transcriptional aberrations affecting different genes in various metabolic pathways and gene dysregulations in neuronal development and differentiation, producing neurotransmission defects. These findings led to attribute an unexpected paramount role in neurodevelopment to HPRT, beside the well-known metabolic functions.