Objective: To determine the effects of hypoxanthine guanine phosphoribosyl transferase (HGprt) deficiency on early brain development in vivo, in a HPRT1-deficient mouse model.

Background: Lesch-Nyhan disease (LND) is a metabolic disorder with a characteristic neurobehavioral phenotype that is dominated by generalized dystonia, specific attention and executive cognitive deficits, and incapacitating self-injurious behavior. LND is caused by a mutation in HPRT1, the gene encoding the purine salvage enzyme HGprt. Microarray-studies in cell models have linked HGprt loss with aberrant expression of transcription factors involved in dopaminergic neuronal development and differentiation. Post-mortem studies in patients confirmed that HGprt-deficient midbrain dopamine neurons fail to express their usual biochemical markers [1]. Therefore, it has been hypothesized that HGprt deficiency causes abnormal dopaminergic development. This hypothesis warrants confirmation in the intact developing brain.

Method: Mouse brains of specific embryonic ages were subjected to immunohistochemistry, focusing on migration and proliferation of midbrain dopaminergic (TH+) cells,* structural organization of radial glia, structural organization of presumptive SN and VTA areas, as well as multiple cortical dopaminergic target areas. Results from HGprt-deficient embryos were compared with wildtype littermate controls.

Results: In the HGprt-deficient developing midbrain, we found aberrant proliferation and migration patterns of early dopaminergic neurons and abnormal structural organization of radial glia fibers supporting this migration, with differences along the rostro-caudal axis. In addition, dopaminergic subpopulation development and structural organization of the presumptive SN and VTA areas were affected. HGprt deficiency was also associated with changes in TH+ innervation of cortical areas and abnormal layering of the cortex.

Conclusion: HGprt-deficiency, generally considered a ‘housekeeping enzyme’, is associated with profound specific abnormalities in the early development of the midbrain dopamine system, as well in other brain areas, including the cerebral cortex. It is suspected that this abnormal neural development results in the neural substrate of the complex neurobehavioral phenotype of LND.

References: [1] Gottle M, Prudente CN, Fu R, et al. Loss of dopamine phenotype among midbrain neurons in Lesch-Nyhan disease. Ann Neurol 2014;76(1):95-107. * Pilot results of this study have been presented at MDS 2016.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/hgprt-deficiency-affects-early-brain-development-in-vivo-in-a-mouse-model-of-lesch-nyhan-disease/