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Hypoxanthine deregulates genes involved in early neuronal development. Implications in Lesch-Nyhan disease pathogenesis

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Neurological manifestations in Lesch-Nyhan disease (LND) are attributed to the effect of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency on the nervous system development. HPRT deficiency causes the excretion of increased amounts of hypoxanthine into the extracellular medium and we hypothesized that HPRT deficiency related to hypoxanthine excess may then lead, directly or indirectly, to transcriptional aberrations in a variety of genes essential for the function and development of striatal progenitor cells. We have examined the effect of hypoxanthine excess on the differentiation of neurons in the well-established human NTERA-2 cl.D1 (NT2/D1) embryonic carcinoma neurogenesis model. NT2/D1 cells differentiate along neuroectodermal lineages after exposure to retinoic acid (RA). Hypoxanthine effects on RA-differentiation were examined by the changes on the expression of various transcription factor genes essential to neuronal differentiation and by the changes in tyrosine hydroxylase (TH), dopamine, adenosine and serotonin receptors (DRD, ADORA, HTR). We report that hypoxanthine excess deregulate WNT4, from Wnt/β-catenin pathway, and engrailed homeobox 1 gene and increased TH and dopamine DRD1, adenosine ADORA2A and serotonin HTR7 receptors, whose over expression characterize early neuro-developmental processes.

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Funding sources

Supported by grant from the Fondo de Investigación Sanitaria del Instituto de Salud Carlos III (Healthcare Research Fund of the Carlos III Health Institute) (FIS, 11/0598).

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None.

This article does not contain any studies with human or animal subjects performed by the any of the authors.

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All authors contribute to the planning, conduct, and reporting of the work described in the article.

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Authors and Affiliations

  1. Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain

    R. J. Torres

  2. Department of Internal Medicine, Metabolic-Vascular Unit, La Paz University Hospital, IdiPaz, Madrid, Spain

    J. G. Puig

  3. Servicio de Bioquímica, Edificio de Laboratorios, Planta 3, Hospital Universitario “La Paz”, Paseo de la Castellana 261, 28046, Madrid, Spain

    R. J. Torres

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  1. R. J. Torres
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  2. J. G. Puig
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Correspondence to R. J. Torres.

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Communicated by: John Christodoulou

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Torres, R.J., Puig, J.G. Hypoxanthine deregulates genes involved in early neuronal development. Implications in Lesch-Nyhan disease pathogenesis. J Inherit Metab Dis 38, 1109–1118 (2015). https://doi.org/10.1007/s10545-015-9854-4

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  • DOI: https://doi.org/10.1007/s10545-015-9854-4

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