ARHI: A new target of galactose toxicity in Classic Galactosemia

Abstract

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 proposed 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 in through evolution, it thus accounts for the lack of clinical phenotypes in the GALT-knockout mice.

Fig. 1

The galactose metabolic pathway is linked to uridine nucleotide and inositol metabolism.

Fig. 2. Up-regulation of ARHI gene transcription in galactose-challenged GALT-deficient cells

Fibroblasts derived from normal (N/N) and galactosemic (G/G) patients were cultured in media containing varying galactose concentration for 24 hours. Quantitative RT-PCR was performed on the mRNA harvested from the respective cultures using primers specific for the primers specific for human ARHI gene and the housekeeping gene GAPDH. This figure illustrated the relative abundance of the amplified ARHI transcripts in different samples by electrophoresing the amplified products on 1% agarose gel and stained with ethidium bromide.