This enzyme enables the body to process a simple sugar called galactose, which is present in small amounts in many foods. Galactose is primarily part of a larger sugar called lactose, which is found in all dairy products and many baby formulas.
Galactosephosphate uridylyltransferase is responsible for one step in a chemical process that breaks down galactose into other molecules that can be used by the body.
Specifically, this enzyme converts a modified form of galactose galactosephosphate to glucose, which is another simple sugar.
Glucose is the main energy source for most cells. This chemical reaction also produces another form of galactose UDP-galactose that is used to build galactose-containing proteins and fats. These modified proteins and fats play critical roles in chemical signaling, building cellular structures, transporting molecules, and producing energy. More than mutations in the GALT gene have been identified in people with the classic form of galactosemia, a condition that causes life-threatening signs and symptoms beginning shortly after birth.
Most of these mutations severely reduce or eliminate the activity of galactosephosphate uridylyltransferase. A shortage of this enzyme prevents cells from processing galactose obtained from the diet.
As a result, galactosephosphate and related compounds can build up to toxic levels in the body. These conditions are each caused by mutations in a particular gene and affect different enzymes involved in breaking down galactose. Classic galactosemia, also known as type I, is the most common and most severe form of the condition.
If infants with classic galactosemia are not treated promptly with a low-galactose diet, life-threatening complications appear within a few days after birth. Affected infants typically develop feeding difficulties, a lack of energy lethargy , a failure to gain weight and grow as expected failure to thrive , yellowing of the skin and whites of the eyes jaundice , liver damage, and abnormal bleeding.
Other serious complications of this condition can include overwhelming bacterial infections sepsis and shock. Affected children are also at increased risk of delayed development, clouding of the lens of the eye cataract , speech difficulties, and intellectual disability.
Females with classic galactosemia may develop reproductive problems caused by an early loss of function of the ovaries premature ovarian insufficiency. Galactosemia type II also called galactokinase deficiency and type III also called galactose epimerase deficiency cause different patterns of signs and symptoms. Galactosemia type II causes fewer medical problems than the classic type. Affected infants develop cataracts but otherwise experience few long-term complications. The signs and symptoms of galactosemia type III vary from mild to severe and can include cataracts, delayed growth and development, intellectual disability, liver disease, and kidney problems.
Classic galactosemia occurs in 1 in 30, to 60, newborns. These genes provide instructions for making enzymes that are essential for processing galactose obtained from the diet. Signs and symptoms of type III galactosemia vary from mild to severe and may include cataracts, stunted growth and development, intellectual disability, liver disease and kidney problems.
These genes encode enzymes that are essential for galactose processing. These enzymes transform galactose into another simple carbohydrate, glucose and other molecules that the body can store or use as energy. The GALT galactosephosphate uridylyltransferase gene, located on the short arm of chromosome 9 9p13 , encodes the enzyme uridylyltransferase galactosephosphate.
This enzyme allows the body to process galactose. Uridylyltransferase galactosephosphate is responsible for a step in a metabolic process that degrades galactose into other molecules that can be used by the body.
Specifically, this enzyme converts a modified form of galactose galactosephosphate to glucose. This chemical reaction also produces another form of galactose UDP-galactose that is used to constitute proteins and fats that contain galactose. These proteins and modified fats play a critical role in chemical signaling, the construction of cellular structures, the transport of molecules and the production of energy.
More than mutations in the GALT gene have been identified in people with the classic form of galactosemia. Most of these genetic changes almost completely eliminate enzyme activity, altering galactose processing. The most frequent mutation replaces the amino acid glutamine with the amino acid arginine at position of the enzyme GlnArg.
Another mutation replaces the amino acid leucine with the amino acid serine at position SerLeu. People with the Duarte variant usually have much milder signs and symptoms of galactosemia because the enzyme retains 5 to 20 percent of its normal activity.
They suggested that a lactose load in combination with the low enzyme level leads to cataract. Brivet et al. Lactosuria is a common finding in pregnant women because of lactose biosynthesis by the mammary glands beginning in the second trimester. Avisar et al. Reports of 14 pregnancies in patients with galactosemia were noted by Waggoner et al.
De Jongh et al. The diagnosis in the mother had been made when she was 2 weeks old, and she had been maintained on a lactose- and galactose-free diet. The pregnancy occurred at the age of 30 years. She had slight mental retardation IQ, She remained on a lactose- and galactose-free diet throughout her pregnancy. This patient was Caucasian; all but one of the previously reported patients were black and may not have had classic galactosemia. The mother in this case was found to be heterozygous for the common QR mutation Since no GALT activity was detected in erythrocytes, a mutation in the other allele was suspected but not found.
The obligate heterozygous offspring of this woman had no apparent adverse effects of the maternal galactosemic state. With the several mutations that have been identified at the GALT locus, the tendency for clinical complications to develop varies from apparent clinical normality in the relatively common Duarte type to perhaps mild symptoms in the SL variant and to the severe galactosemia syndrome in the 'classic,' Indiana, and Rennes variants Hammersen et al.
Beutler et al. This new form was discovered in the course of a screening program. Patients with the Duarte variant of galactosemia are usually healthy, despite functional and structural abnormality in their galactosephosphate uridylyltransferase. An 8-month-old boy who had jaundice and liver enlargement during the first 2 months was reported by Kelly et al. He was homozygous for the Duarte variant. Both parents and 2 sisters were carriers. Surgical biopsy of the liver showed marked fatty infiltration, periportal fibrosis, and cirrhosis.
His subsequent development was normal. Improvement, the authors suggested, may have been due to maturation of the enzyme. Two similar cases had been reported. Using G for the allele causing classic galactosemia and D for the Duarte allele ND; rs ; The Duarte allele is associated with an isoform of the enzyme that has more acidic pI than normal.
Langley et al. Subsequently, Kozak et al. Carney et al. Another type of galactosemia is associated with the SL mutation The difference in behavior of the metabolism of galactose in these patients may be due to the development of an alternative pathway Cuatrecasas and Segal, Other relevant observations on the SL variant were reported by Baker et al.
Mellman et al. Heterogeneity was demonstrated by the studies of Segal and Cuatrecasas Patients with the SL mutation have a less severe phenotype De Jongh et al.
On the basis of a screening of newborns in Massachusetts, Shih et al. Both infants died with E. Since E. Gitzelmann et al. They concluded that color Doppler sonography is the method of choice for the diagnosis of an open duct; pulsed wave Doppler sonography was recommended for pathophysiologic characterization of splanchnic venous return.
At age 3. Long-term results of treatment have been disappointing; IQ is low in many despite early and seemingly adequate therapy. See, for example, the retrospective study by Schweitzer et al. The cause of the unsatisfactory outcome of seemingly good control of galactose intake and the disturbances in long-term development despite treatment are unclear. An international survey of the long-term results of treating galactosemia in cases yielded overall unsatisfactory results which could not be related to variables such as delayed diagnosis or poor dietary compliance Waggoner et al.
Webb et al. They reported that a simplified breath test evaluating total body galactose oxidation is a sensitive predictor of verbal dyspraxia in patients with galactosemia. Of 24 patients who underwent a formal speech evaluation, 15 had verbal dyspraxia. Using different chromosomal aberrations involving 9p and dosage effects, Sparkes et al.
Dagna Bricarelli et al. A patient with deletion of 9pter-p22 had normal values; a patient with deletion of 9pp had decrease in both values. The authors interpreted the findings as indicating location of the GALT locus in the 9p21 band. Shih et al. By deletion mapping, Kondo and Nakamura corroborated the 9p13 localization. Nadler et al.
They interpreted this as evidence of interallelic complementation. Tedesco and Mellman demonstrated that in galactosemia galP uridylyltransferase is immunologically intact although enzymatically defective; thus, a structural gene mutation is involved. Segal et al. The galactosemic patients formed labeled UDPglucose, implying that the classic galactosemic possesses residual GALT activity or some other pathway for forming UDPglucose from galactose.
Feillet et al. Laboratory studies showed increased citrulline and increased levels of other amino acids, suggesting the diagnosis of citrin deficiency There were low levels of urinary citric acid cycle intermediates, and administration of citrate resulted in improvement in liver function.
Introduction of oral galactose resulted in vomiting, galactose aversion, and hepatic dysfunction, consistent with classic galactosemia, and the diagnosis was confirmed by molecular analysis. Two common mutations, QR In the black population, SL Elsas et al.
A total of 12 new and 21 previously reported rare mutations were found. Among the novel group of 12 new mutations, an unusual biochemical phenotype was found in a family in which the newborn proband had classic galactosemia. From the father, he had inherited 2 mutations in cis: asn to asp ND; From the mother, he had inherited a mutation in the splice acceptor site of intron C of the GALT gene.
The GALT activity in erythrocytes of the father, who was heterozygous for the double mutation, was near normal. Surprisingly, her erythrocytes had normal GALT activity. The latter mutation is a frequent basis of the Duarte variant; the former was a new mutation found in this study. The chromosome with only one mutation, ND, came from the proband's mother.
One of the fundamental questions concerning expression and function of dimeric enzymes involves impact of naturally occurring mutations on subunit assembly and heterodimer activity.
The question is of particular interest for GALT, the enzyme deficient in galactosemia, because most patients are compound heterozygotes rather than true molecular homozygotes.
Furthermore, the broad range of phenotypic severity observed in these patients raises the possibility that allelic combination, not just allelic constitution, may play some role in determining outcome. Elsevier et al. In a yeast system, they found that both homodimers and heterodimers formed involving each of the mutant subunits tested, and that both heterodimer pools retained substantial enzymatic activity. The yeast system they described was promoted as a model for similar studies of other complexes composed of multiple subunits.
The experiments of Elsevier et al. Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei
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