Objective: To determine the in vivo effects of hypoxanthine-guanine phosphoribosyl transferase (HGprt) deficiency on dopaminergic neurodevelopment in a genetic mouse model of Lesch-Nyhan disease (LND).

Background: LND, due to deficiency of the purine salvage enzyme HGprt, is associated with dopamine loss in the basal ganglia. The clinical phenotype develops over the first years of life, and is dominated by dystonia, cognitive dysfunction and self-injurious behavior. There is no cure, and the mechanisms by which HGprt deficiency causes dopamine depletion remain elusive. Previous cell model studies have suggested that HGprt deficiency affects neural programming of early midbrain dopamine neurons. Here, we aim to characterize the effects of HGprt loss on dopaminergic neuronal development in vivo in a mouse model for LND.

Methods: Brains of HGprt-deficient and normal male C57BL6 mouse embryos at stage E14.5 were subjected to immunohistochemistry for markers of dopamine synthesis (e.g. TH), migration and proliferation (e.g. BrdU; pregnant mothers were injected 2 days prior to sacrifice) and dopaminergic programming (e.g. En1/2, Nurr1). Furthermore, RNAs extracted from homogenates of wild-type whole mouse brains at 6 embryonic (E10.5–E18.5) and 6 postnatal (P0–P140) time points were subjected to qPCR to determine levels of HGprt mRNA expression over time.

Results: In E14.5 HGprt-deficient embryos, a cell-type specific significant decrease in the total number of TH-positive cells was observed in the mesencephalon, with an increase in cell division. Furthermore, cellular alignment was abnormal in the HGprt-deficient mice, and cells appeared to prematurely leave the midline migrational paths. Over time, HGprt expression levels are relatively constant during embryogenesis in wild-type whole mouse brains, but show a marked increase, up to over four-fold, during the first 3-4 weeks after birth.

Conclusions: These findings demonstrate that HGprt deficiency in mice is associated with maldevelopment of the dopaminergic system during embryogenesis that may involve abnormal proliferation, migration, and neural programming. Moreover, the brain’s demand for HGprt function appears to increase markedly after birth, i.e. when – in patients – the clinical symptoms arise. Further studies will focus on the specific embryonic but also postnatal timing of abnormalities.

Preliminary results were presented at MDS 2014.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/deficiency-of-hgprt-in-lesch-nyhan-disease-is-associated-with-abnormal-dopaminergic-neurodevelopment-in-vivo/