MicroRNAs: tools of mechanistic insights and biological therapeutics discovery for the rare neurogenetic syndrome Lesch-Nyhan disease (LND)

Adv Genet. 2015:90:103-131. doi: 10.1016/bs.adgen.2015.06.001. Epub 2015 Jul 20.


MicroRNAs (miRNAs) are small regulatory RNAs that modulate the translation of mRNA. They have emerged over the past few years as indispensable entities in the transcriptional regulation of genes. Their discovery has added additional layers of complexity to regulatory networks that control cellular homeostasis. Also, their dysregulated pattern of expression is now well demonstrated in myriad diseases and pathogenic processes. In the current review, we highlight the role of miRNAs in Lesch-Nyhan disease (LND), a rare neurogenetic syndrome caused by mutations in the purine metabolic gene encoding the hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme. We describe how experimental and biocomputational approaches have helped to unravel genetic and signaling pathways that provide mechanistic understanding of some of the molecular and cellular basis of this ill-defined neurogenetic disorder. Through miRNA-based target predictions, we have identified signaling pathways that may be of significance in guiding biological therapeutic discovery for this incurable neurological disorder. We also propose a model to explain how a gene such as HPRT, mostly known for its housekeeping metabolic functions, can have pleiotropic effects on disparate genes and signal transduction pathways. Our hypothetical model suggests that HPRT mRNA transcripts may be acting as competitive endogenous RNAs (ceRNAs) intertwined in multiregulatory cross talk between key neural transcripts and miRNAs. Overall, this approach of using miRNA-based genomic approaches to elucidate the molecular and cellular basis of LND and guide biological target identification might be applicable to other ill-defined rare inborn-error metabolic diseases.

Keywords: Lesch–Nyhan disease (LND); MicroRNAs; Therapeutic discovery; Transcription regulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Gene Expression Regulation
  • Humans
  • Hypoxanthine Phosphoribosyltransferase / genetics*
  • Lesch-Nyhan Syndrome / genetics
  • Lesch-Nyhan Syndrome / therapy*
  • MicroRNAs / therapeutic use*
  • RNA, Messenger / genetics


  • MicroRNAs
  • RNA, Messenger
  • Hypoxanthine Phosphoribosyltransferase