Genetic Disorders – Development
Kidney International (2004) 66, 959–963; doi:10.1111/j.1523-1755.2004.00842.x
Evaluation of mutation screening as a first line test for the diagnosis of the primary hyperoxalurias1
GILL RUMSBY, EMMA WILLIAMS and MARION COULTER-MACKIE
Clinical Biochemistry, UCL Hospitals, London, United Kingdom; and Department of Pediatrics, University of British Columbia and British Columbia Children's Hospital, Vancouver, Canada
Correspondence: Dr Gill Rumsby, UCL Hospitals Clinical Biochemistry, 60 Whitfield St, London W1T 4EU, United Kingdom. E-mail:gill.rumsby@uclh.nhs.uk
1The nomenclature used in this paper is based on that recommended by Antonarakis SE, and the Nomenclature Working Group (1998): Recommendations for a nomenclature system for human gene mutations. Hum Mutat 11:1–3, 1998, where "c" denotes cDNA sequence and nucleotide numbering uses the "A" of the ATG translation initiation start site as +1.
Received 4 February 2004; Revised 29 March 2004; Accepted 5 April 2004.
Abstract
Evaluation of mutation screening as a first line test for the diagnosis of the primary hyperoxalurias.
Background
A definitive diagnosis of primary hyperoxaluria type 1 (PH1) and primary hyperoxaluria type 2 (PH2) requires the measurement of alanine:glyoxylate aminotransferase (AGT) and glyoxylate reductase (GR) activities, respectively, in a liver biopsy. We have evaluated a molecular genetic approach for the diagnosis of these autosomal-recessive diseases.
Methods
Polymerase chain reaction (PCR) was used to detect three common mutations in the AGXT gene (c.33_34insC, c.508G>A, and c.731T>C) and one, c.103delG, in the GRHPR gene in DNA samples from 365 unrelated individuals referred for diagnosis of PH1 and/or PH2 by liver enzyme analysis.
Results
One or more of these mutations was found in 183 (68.8%) biopsy proven cases of PH1 and PH2 with a test negative predictive value of 62% and 2%, respectively. 102 (34.1%) patients were homozygous or compound heterozygous, making a molecular diagnosis possible. Age of onset and presenting features were similar in patients homozygous for any of the four mutations. Of the AGXT homozygotes, only the c.508G>A mutant was associated with significant AGT catalytic activity and in two of these activity was in the low normal range, possibly reflecting variation in mitochondrial content of the biopsy as this particular mutation is associated with mitochondrial mistargeting.
Conclusion
Limited mutation analysis can provide a useful first line test for PH1 and PH2 in patients in whom primary hyperoxaluria is suspected and in whom secondary causes have been excluded. Those patients in whom a single mutation, or no mutation, is found can then be selectively targeted for liver biopsy.
Keywords:
primary hyperoxaluria, mutation, screening, molecular diagnosis, glyoxylate reductase, alanine:glyoxylate aminotransferase
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