Involvement of endoplasmic reticulum stress in a novel Classic Galactosemia model

Tatiana I. Slepak, Manshu Tang, Vladlen Z. Slepak, Kent Lai

Research output: Contribution to journalArticlepeer-review

54 Scopus citations


Inherited deficiency of galactose-1-phosphate uridyltransferase (GALT) activity in humans leads to a potentially lethal disorder called Classic Galactosemia. It is well known that patients often accumulate high levels of galactose metabolites such as galactose-1-phosphate (gal-1-p) in their tissues. However, specific targets of gal-1-p and other accumulated metabolites remain uncertain. In this study, we developed a new model system to study this toxicity using primary fibroblasts derived from galactosemic patients. GALT activity was reconstituted in these primary cells through lentivirus-mediated gene transfer. Gene expression profiling showed that GALT-deficient cells, but not normal cells, responded to galactose challenge by activating a set of genes characteristic of endoplasmic reticulum (ER) stress. Western blot analysis showed that the master regulator of ER stress, BiP, was up-regulated at least threefold in these cells upon galactose challenge. We also found that treatment of these cells with galactose, but not glucose or hexose-free media reduced Ca2+ mobilization in response to activation of Gq-coupled receptors. To explore whether the muted Ca2+ mobilization is related to reduced inositol turnover, we discovered that gal-1-p competitively inhibited human inositol monophosphatase (hIMPase1). We hypothesize that galactose intoxication under GALT-deficiency resulted from accumulation of toxic galactose metabolite products, which led to the accumulation of unfolded proteins, altered calcium homeostasis, and subsequently ER stress.

Original languageEnglish (US)
Pages (from-to)78-87
Number of pages10
JournalMolecular Genetics and Metabolism
Issue number1-2
StatePublished - Sep 2007


  • Endoplasmic reticulum stress
  • Galactose-1-phosphate
  • Galactosemia
  • GRP78
  • Inositol monophosphatase
  • Unfolded protein response

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Endocrinology, Diabetes and Metabolism


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