Adaptive evolution of heparanase in hypoxia-tolerant Spalax: Gene cloning and identification of a unique splice variant

Nicola J. Nasser, Eviatar Nevo, Itay Shafat, Neta Ilan, Israel Vlodavsky, Aaron Avivi

Research output: Contribution to journalArticlepeer-review


Heparan sulfate (HS) side chains of HS proteoglycans bind to and assemble extracellular matrix proteins and play important roles in cell-cell and cell-extracellular matrix interactions. HS chains bind a multitude of bioactive molecules and thereby function in the control of multiple normal and pathological processes. Enzymatic degradation of HS by heparanase, a mammalian endoglycosidase, affects the integrity and functional state of tissues and is involved in, among other processes, inflammation, angiogenesis, and cancer metastasis. Here, we report the cloning of heparanase from four Israeli species of the blind subterranean mole rat (Spalax ehrenbergi superspecies), 85% homologous to the human enzyme. Unlike its limited expression in human tissues, heparanase is highly expressed in diverse Spalax tissues. Moreover, we have identified a unique splice variant of the Spalax enzyme lacking 16 aa encoded by exon 7. This deletion resulted in a major defect in trafficking and processing of the heparanase protein, leading to a loss of its enzymatic activity. Interspecies variation was noted in the sequence and in the expression of the splice variant of the heparanase gene in blind mole rats living under different ecogeographical stresses, indicating a possible role in adaptation to stress in Spalax evolution.

Original languageEnglish
Pages (from-to)15161-15166
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number42
StatePublished - 18 Oct 2005


  • Alternative splicing
  • Angiogenesis
  • Blind mole rat
  • Cancer
  • Heparan sulfate

ASJC Scopus subject areas

  • General


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