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.

Ovarian function in girls and women with GALT‐deficiency galactosemia

“…Recently, the human tumor suppressor gene aplysia ras homolog 1 ( ARHI), which is involved in ovarian folliculogenesis, was proposed as a possible target of toxicity in classic galactosemia (Lai et al 2008). This gene is missing in rodents (Fitzgerald and Bateman 2004), and re-expression of this gene in mice causes failure of ovarian follicular maturation, poor growth, and impaired Purkinje cell development (Xu et al 2000).…”

Galactose toxicity in animals

“…These authors did not consider the possibility that the target(s) of galactose toxicity in human galactosemic patients could be absent in rodents, or the likelihood that these toxicity targets in mice are less susceptible to the toxic galactose metabolites. We recently identified a human gene called ARHI (aplysia ras homolog I) as a new a target of galactose toxicity in galactosemic patients [166]. We found that this gene was over-expressed in cultured dermal fibroblasts from patients with no GALT genes [77].…”

“…We found that this gene was over-expressed in cultured dermal fibroblasts from patients with no GALT genes [77]. When these cells (and controls with GALT) were challenged with galactose, ARHI was increased 10-fold over a 24-hour period [166] in the GALT-deficient cells. Interestingly, over-expression of the ARHI transgene in a normal mouse model caused failure of folliculogenesis, loss of Purkinje cells in the cerebellar cortex, and stunted growth [167], all prevalent clinical complications seen in GALT-deficient patients [25].…”

Innovative therapy for Classic Galactosemia — Tale of two HTS

“…Recently, we have identified a human gene called aplysia ras homolog I ( ARHI ) that is absent in rodents due to an ancestral recombination event [131]. Interestingly, this tumor suppressor gene was found to be abnormally up-regulated in patients with Classic Galactosemia [132]. We have proposed that the lack of ARHI gene in rodents may explain the absence of human disease phenotypes in the original GALT -KO mice.…”

“…This could potentially decrease cellular PIP 2 content and adversely affect normal AKT function. Blockage of galactose metabolism has also been shown to up-regulate ARHI gene expression [132], which negatively regulate AKT activity in the cells. (Abbreviations: PIP 2 : phosphatidylinositol-4,5-biphosphate; IP 3 : inositol-1,4,5-triphosphate; IP 2 : inositol bisphosphate; IP 1 : inositol monophosphate; PIP 3 : phosphatidylinositol-3,4,5-triphosphate; SMIT1: Na + / myo -inositol transporter; IMPase: inositol monophosphatase; P13K: phosphatidylinositol 3-kinase; GPCR: G-protein coupled receptor.…”