A Mouse Model of Galactose-1-Phosphate Uridyl Transferase Deficiency

doi:10.1006/bmme.1996.0057

Biochemical and Molecular Medicine

Volume 59, Issue 1, October 1996, Pages 7-12

Biochemical and Mole...

https://doi.org/10.1006/bmme.1996.0057 Get rights and content

Abstract

Galactose-1-phosphate uridyl transferase (GALT) deficiency causes classical galactosemia in humans. Mice deficient in this enzyme were created by gene targeting. GALT-deficient mice develop biochemical features similar to those seen in humans with GALT deficiency, but fail to develop the pattern of acute toxicity seen in newborns with classical galactosemia. This study suggests that alternative routes of galactose metabolism are important in the pathogenesis of galactosemia.

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Cited by (78)

Alterations of galactose metabolism caused by deficit of galactose-1-phosphate uridylyltransferase activity: An overview of galactosemia type I
2019, Molecular Nutrition Carbohydrates
Galactosemia type I is caused by a deficiency of the galactose-1-phosphate uridylyltransferase enzyme, encoding by the GALT gene. This pathology is inherited in an autosomal recessive pattern. Following galactose intake by galactosemic neonates, a toxic buildup of galactose metabolism intermediates is produced. Promptly, various signs appeared such as lethargy, poor feeding, jaundice, and hepatomegaly. Treatment is relatively easy to achieve to prevent acute symptoms and save the baby's life. However, even when patients undergo lifelong galactose dietary restrictions, some subjects develop mild to severe long-term complications. The mutational spectrum is characterized by allele heterogeneity, where few alleles have high frequency and a clear ethnic distribution. Missense mutations are the most common variants and are distributed along the whole GALT gene, altering functional and structural features of the enzyme. Dietary treatments consist of eliminating lactose- and galactose-rich foods and supplying formulas of soy milk. This diet should be maintained through the whole life of the patient. In contrast, the diet should be absolutely normal in the Duarte form of galactosemia. Experts reached a consensus and recommended the consumption of fruits, vegetables, legumes, unfermented soy products, and hard chesses.
Hereditary galactosemia
2018, Metabolism: Clinical and Experimental
Citation Excerpt :
The intracellular elevation of galactitol induces hyperosmotic and oxidative stress [7–9], which has been pointed out as the causative agent of cataracts in GALT- and GALK-deficiencies. Furthermore, the mouse exhibits low aldose reductase expression/activity in the lens, and indeed neither the GALK- nor the GALT-deficient mouse develops cataracts [10,11]. Pseudotumor cerebri is also hypothesized to be due to accumulation of galactitol.
Hereditary galactosemia is an inborn error of carbohydrate metabolism. Galactose is metabolized by Leloir pathway enzymes; galactokinase (GALK), galactose-1-phosphate uridylyltransferase (GALT) and UDP-galactose 4-epimerase (GALE). The defects in these enzymes cause galactosemia in an autosomal recessive manner. The severe GALT deficiency, or classic galactosemia, is life-threatening in the newborn period. The treatment for classic galactosemia is dietary restriction of lactose. Although implementation of lactose restricted diet is efficient in resolving the acute complications, it is not sufficient to prevent long-term complications affecting the brain and female gonads, the two main target organs of damage. Implementation of molecular genetics diagnostic tools and GALT enzyme assays are instrumental in distinguishing classic galactosemia from clinical and biochemical variant forms of GALT deficiency. Better understanding of mechanisms responsible for the phenotypic variation even within the same genotype is essential to provide appropriate counseling for families. Utilization of a lactose restricted diet is also recommended for GALK deficiency and some rare forms of GALE deficiency. Novel modes of therapies are being explored; they may be beneficial if access issues to the affected tissues are circumvented and optimum use of therapeutic window is achieved.
The molecular basis of galactosemia — Past, present and future
2016, Gene
Galactosemia, an inborn error of galactose metabolism, was first described in the 1900s by von Ruess. The subsequent 100 years has seen considerable progress in understanding the underlying genetics and biochemistry of this condition. Initial studies concentrated on increasing the understanding of the clinical manifestations of the disease. However, Leloir's discovery of the pathway of galactose catabolism in the 1940s and 1950s enabled other scientists, notably Kalckar, to link the disease to a specific enzymatic step in the pathway. Kalckar's work established that defects in galactose 1-phosphate uridylyltransferase (GALT) were responsible for the majority of cases of galactosemia. However, over the next three decades it became clear that there were two other forms of galactosemia: type II resulting from deficiencies in galactokinase (GALK1) and type III where the affected enzyme is UDP-galactose 4′-epimerase (GALE). From the 1970s, molecular biology approaches were applied to galactosemia. The chromosomal locations and DNA sequences of the three genes were determined. These studies enabled modern biochemical studies. Structures of the proteins have been determined and biochemical studies have shown that enzymatic impairment often results from misfolding and consequent protein instability. Cellular and model organism studies have demonstrated that reduced GALT or GALE activity results in increased oxidative stress. Thus, after a century of progress, it is possible to conceive of improved therapies including drugs to manipulate the pathway to reduce potentially toxic intermediates, antioxidants to reduce the oxidative stress of cells or use of “pharmacological chaperones” to stabilise the affected proteins.
Intracerebroventricular d-galactose administration impairs memory and alters activity and expression of acetylcholinesterase in the rat
2016, International Journal of Developmental Neuroscience
Tissue accumulation of galactose is a hallmark in classical galactosemia. Cognitive deficit is a symptom of this disease which is poorly understood. The aim of this study was to investigate the effects of intracerebroventricular administration of galactose on memory (inhibitory avoidance and novel object recognition tasks) of adult rats. We also investigated the effects of galactose on acetylcholinesterase (AChE) activity, immunocontent and gene expression in hippocampus and cerebral cortex. Wistar rats received a single injection of galactose (4 mM) or saline (control). For behavioral parameters, galactose was injected 1 h or 24 h previously to the testing. For biochemical assessment, animals were decapitated 1 h, 3 h or 24 h after galactose or saline injection; hippocampus and cerebral cortex were dissected. Results showed that galactose impairs the memory formation process in aversive memory (inhibitory avoidance task) and recognition memory (novel object recognition task) in rats. The activity of AChE was increased, whereas the gene expression of this enzyme was decreased in hippocampus, but not in cerebral cortex. These findings suggest that these changes in AChE may, at least in part, to lead to memory impairment caused by galactose. Taken together, our results can help understand the etiopathology of classical galactosemia.
Disorders of the Gonads, Genital Tract, and Genitalia
2013, Emery and Rimoin's Principles and Practice of Medical Genetics
Genetics of Female Infertility in Humans
2013, Emery and Rimoin's Principles and Practice of Medical Genetics

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Regular ArticleA Mouse Model of Galactose-1-Phosphate Uridyl Transferase Deficiency

Abstract

Regular Article
A Mouse Model of Galactose-1-Phosphate Uridyl Transferase Deficiency