Objective: To determine the effect of hypoxanthine guanine phosphoribosyl transferase (HGprt) deficiency on mouse brain RNA expression patterns in multiple brain areas, during embryonic development and juvenile period.

Background: Lesch-Nyhan disease (LND) is a metabolic disorder with a characteristic neurobehavioral phenotype dominated by generalized dystonia, specific 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, immunohistochemistry studies in HGprt-deficient mice [1] and post-mortem studies in patients [2] have suggested that HGprt deficiency causes abnormal neural development and differentiation of particularly the dopamine system. However, prior studies have failed to elucidate the molecular mechanism underlying abnormal brain development due to HGprt deficiency.

Method: HGprt deficient as well as control cryo-punched mouse brain samples, at embryonic age E16.5 (7 brain areas) and postnatal age P30 (8 brain areas), were subjected to RNA sequencing in triplicate. Transcript expression was quantified (Salmon), differential expression analyzed (Deseq2) and higher-level biological functions interpreted using gene set enrichment and pathway analyses (KEGG, Gene Ontology).

Results: When the sequence data are clustered into midbrain, subcortical and cortical regions, pilot pathway analyses indicate that HGprt deficiency is associated with clear abnormalities in gene expression that appear often specific for both brain region and age. Functional analysis suggested significant roles for neuroactive ligand-receptor interaction (KEGG) and aspects of ion channel function at synaptic levels (Gene Ontology).

Conclusion: Deficiency of HGprt, generally considered a global ‘housekeeping enzyme’, is associated with temporal and spatial abnormalities in RNA expression patterns that suggest specific abnormal neuronal function. These data can be used for hypothesis generation and testing, in HPRT1 deficient cell or animal models, to elucidate the molecular mechanisms underlying the abnormal brain development in Lesch-Nyhan disease.

References: [1] Witteveen JS, Loopstok SR, Luque Ballesteros L, et al. HGprt deficiency affects early brain development in vivo in a mouse model of Lesch-Nyhan disease. Abstract at MDS 2019. [2] 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.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/hgprt-deficient-brain-rna-expression-patterns-reveal-specific-abnormalities-related-to-neuronal-function-in-a-mouse-model-of-lesch-nyhan-disease/