ARHI: A new target of galactose toxicity in Classic Galactosemia

In humans, deficiency of galactose-1-phosphate uridyltransferase (GALT) activity can lead to a potentially lethal disease called Classic Galactosemia. Although a galactose-restricted diet can prevent the acute lethality associated with the disorder, chronic complications persist in many well-treated patients. Approximately 85% of young women with Classic Galactosemia experience hypergonadotropic hypogonadism and premature ovarian failure (POF). Others suffer from mental retardation, growth restriction, speech dyspraxia, and ataxia. Despite decades of intense biochemical characterization, little is known about the molecular etiology, as well as the chronology of the pathological events leading to the poor outcomes. Several hypotheses have been proposed, most of which involved the accumulation of the intermediates and/or the deficit of the products, of the blocked GALT pathway. However, none of these hypotheses satisfactorily explained the absence of patient phenotypes in the GALT-knockout mice. Here we propose that the gene encoded the human tumor suppressor gene aplysia rashomolog I (ARHI) is a target of toxicity in Classic Galactosemia, and because ARHI gene is lost in rodents through evolution, it thus accounts for the lack of clinical phenotypes in the GALT-knockout mice.