Molecular heterogeneity of classical and duarte galactosemia: Mutation analysis by denaturing gradient gel electrophoresis

Greber‐Platzer, Susanne; Guldberg, Per; Scheibenreiter, S; Item, Chike B.; Schuller, Erich; Patel, Neel; Strobl, Wolfgang

doi:10.1002/(sici)1098-1004(1997)10:1<49::aid-humu7>3.0.co;2-h

Cited by 48 publications

(21 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although two common mutations, Q188R and K285N, account for approximately 69 -88% of galactosemia alleles in Caucasian populations, over 170 different rare sequence changes have been described so far (7)(8)(9)(10)(11).…”

contrasting

confidence: 74%

Mutations at the Galactose-1-P-Uridyltransferase Gene in Infants with a Positive Galactosemia Newborn Screening Test

et al. 2002

View full text Add to dashboard Cite

Newborn screening for galactosemia yields a high number of false-positive results. Confirmatory DNA testing for unknown galactosemia mutations on the initial positive sample using novel techniques of mutation detection tenders itself to reduce the recall rate. The potential benefits of confirmatory DNA testing, however, could be offset by the detection of a high percentage of galactosemia carriers, Duarte/galactosemia compound heterozygotes, and infants with benign sequence changes in the galactose-1-phosphate uridyltransferase (GALT) gene among infants with a positive biochemical screening test. Our aim was to determine the frequency and allelic distribution of all sequence changes in the GALT gene in 110 newborns with a positive total galactose screening test among 43,688 Austrian newborns screened consecutively. We found that only 20 of the 110 probands carried at least one known or novel candidate galactosemia mutation (one galactosemia homozygote, 7 Duarte/galactosemia compounds, 12 carriers) as judged by denaturing gradient gel electrophoresis and cleavage fragment length polymorphism analysis. Four novel galactosemia candidate mutations (Q9H, A46fsdelCAGCT, M129T, L342I) were identified. Sixty-seven probands had no detectable sequence changes and 23 carried only the benign Duarte or Los Angeles variant alleles or silent mutations. We conclude that a rapid and automatable confirmation test for unknown GALT mutations, e.g. on a high-density oligonucleotide array basis, has the potential to lower the recall rate of galactosemia screening in our population by about five-fold from 0.25 to 0.046%. Further research, however, will be required before the development of such a test can be advocated. Classical galactosemia (McKusick 230400) is an autosomal recessive inborn error of carbohydrate metabolism caused by a deficiency of GALT occurring with an incidence of 1:40,000 -60,000 in Caucasian populations (1). Newborn screening and dietary galactose restriction prevent the life-threatening neonatal symptoms of galactosemia. Despite dietary treatment, the majority of affected children develop long-term complications including mental retardation, speech deficits, and ovarian failure.Galactosemia screening by microbiological or biochemical tests for elevated blood galactose/galactose-1-P and/or reduced GALT activity yields a high rate of false positives (2). Only 1 in about 190 infants recalled in galactosemia screening programs across the United States will actually have galactosemia (3). Because of the potentially rapid and fatal course of the disease, newborns with positive test results have to be recalled urgently. This causes substantial anxiety among the families concerned (4) and increases the workload of the screening centers.DNA confirmatory testing for common mutations on the original dried blood spot with a positive initial biochemical screening result has been used to reduce the number of false positives in screening programs for cystic fibrosis (5) and hemoglobinopathies (6). Although two common mutation...

show abstract

contrasting

confidence: 74%

Mutations at the Galactose-1-P-Uridyltransferase Gene in Infants with a Positive Galactosemia Newborn Screening Test

et al. 2002

View full text Add to dashboard Cite

show abstract

“…28 The p.Q188R mutation is considered severe, with no GALT activity in human erythrocytes in the homozygous state. 10 p.Q188R also accounts for approximately 50 to 58% of the mutant alleles in Hispanics of Mexican ancestry. 29 The IVS2-2AϾG is rare but has been described in Hispanic populations and is …”

Section: ј-Cactgtctctcttctttctgtcaggggctcccacaggatcagaggctggggccaactmentioning

confidence: 99%

“…9 The p.K285N mutation is also severe but has a frequency of approximately 26% in mutant alleles in Eastern Europeans. 10,30 The p.S135L is the most common mutation in African Americans and accounts for 50% of the mutations observed in that population. This mutation is usually associated with a milder clinical phenotype than p.Q188R, which is the second most common mutation in the Black population.…”

Section: Analysis Of Common Mutations In Galt 621mentioning

confidence: 99%

“…The LA variant p.L218L (c.652CϾT) in cis with the p.N314D (c.940AϾG) increases the enzyme activity to approximately 130%. 10 The Duarte (D) variant (p.N314D, c.940AϾG) reduces enzyme activity by approximately 25% and is found in approximately 5% of the general US population. 11,12 This variant is also in cis with the deletion c.-119-Ͼ-116delGTCA in the 5Ј-untranslated region of the GALT gene, thus also affecting a regulatory region.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Simultaneous Amplification, Detection, and Analysis of Common Mutations in the Galactose-1-Phosphate Uridyl Transferase Gene

Jama

Nelson²,

Mao

et al. 2007

The Journal of Molecular Diagnostics

View full text Add to dashboard Cite

Classic galactosemia is an autosomal recessive inherited error of galactose metabolism. It is caused by lack of galactose-1-phosphate uridyl transferase, an enzyme that is required to metabolize galactose-1-phosphate to uridine diphosphate galactose. The build up of galactose-1-phosphate is toxic at high levels and can damage the liver, brain, eyes, and other vital organs. Over 200 mutations have been identified in affected individuals. We describe an assay to identify nine target mutations or variants in the galactose-1-phosphate uridyl transferase gene, namely p.Q188R, p.S135L, p.K285N, p.L195P, p.T138M, p.Y209C, IVS2-2 A>G, p.L218L, and p.N314D. A single long-range PCR is followed by a multiplexed nucleotide extension assay (single nucleotide extension) and capillary electrophoresis to detect simultaneously all nine target mutations/variants. Fiftyfour previously characterized samples (47 clinical samples and seven controls) gave a 100% concordance. We also report a nontarget novel mutation, p.L192X, and its profile using single nucleotide extension. This assay can complement the enzyme activity assay and identify familial mutations for testing additional family members. (J Mol Diagn 2007, 9:618 -623;

show abstract

“…These individuals, so-called DG variants (DG, 4 Duarte galactosemia), typically manifest about 25% of wild-type GALT activity and can be detected through newborn screening (1)(2)(3)(4). Although these babies have increased concentrations of galactose metabolites, no reports have indicated that such individuals develop symptoms of classic galactosemia (5 ).…”

mentioning

confidence: 99%

Monitoring of Biochemical Status in Children with Duarte Galactosemia: Utility of Galactose, Galactitol, Galactonate, and Galactose 1-Phosphate

et al. 2010

View full text Add to dashboard Cite

BACKGROUND: Duarte galactosemia (DG) is frequently detected in newborn-screening programs. DG patients do not manifest the symptoms of classic galactosemia, but whether they require dietary galactose restriction is controversial. We sought to assess the relationships of selected galactose metabolites (plasma galactose, plasma galactitol, erythrocyte (RBC) galactitol, RBC galactonate, and urine galactitol and galactonate) to RBC galactose 1-phosphate (Gal-1-P), dietary galactose intake, and neurodevelopmental/clinical outcomes in DG children.

show abstract

Molecular heterogeneity of classical and duarte galactosemia: Mutation analysis by denaturing gradient gel electrophoresis

Cited by 48 publications

References 18 publications

Mutations at the Galactose-1-P-Uridyltransferase Gene in Infants with a Positive Galactosemia Newborn Screening Test

Mutations at the Galactose-1-P-Uridyltransferase Gene in Infants with a Positive Galactosemia Newborn Screening Test

Simultaneous Amplification, Detection, and Analysis of Common Mutations in the Galactose-1-Phosphate Uridyl Transferase Gene

Monitoring of Biochemical Status in Children with Duarte Galactosemia: Utility of Galactose, Galactitol, Galactonate, and Galactose 1-Phosphate

Contact Info

Product

Resources

About