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Comprehensive Mutation Screening in 55 Probands with Type 1 Primary Hyperoxaluria Shows Feasibility of a Gene-Based Diagnosis

Carla G. Monico^*, Sandro Rossetti, Heidi A. Schwanz, Julie B. Olson^*, Patrick A. Lundquist, D. Brian Dawson, Peter C. Harris and Dawn S. Milliner^*

^* Mayo Clinic Hyperoxaluria Center and Department of Biochemistry and Molecular Biology, Division of Nephrology, and Clinical Molecular Genetics Laboratory, Mayo Clinic College of Medicine, Rochester, Minnesota; and Luther College, Decorah, Iowa

Address correspondence to: Dr. Carla G. Monico, Mayo Clinic Hyperoxaluria Center and Departments of Internal Medicine and Pediatric and Adolescent Medicine, Divisions of Nephrology and Pediatric Nephrology, Mayo Clinic College of Medicine, Rochester, MN 55902. Phone: 507-266-1045; Fax: 507-266-7891; E-mail: monico.carla{at}mayo.edu

Received for publication November 10, 2006. Accepted for publication March 14, 2007.

Mutations in AGXT, a locus mapped to 2q37.3, cause deficiency of liver-specific alanine:glyoxylate aminotransferase (AGT), the metabolic error in type 1 primary hyperoxaluria (PH1). Genetic analysis of 55 unrelated probands with PH1 from the Mayo Clinic Hyperoxaluria Center, to date the largest with availability of complete sequencing across the entire AGXT coding region and documented hepatic AGT deficiency, suggests that a molecular diagnosis (identification of two disease alleles) is feasible in 96% of patients. Unique to this PH1 population was the higher frequency of G170R, the most common AGXT mutation, accounting for 37% of alleles, and detection of a new 3' end deletion (Ex 11_3'UTR del). A described frameshift mutation (c.33_34insC) occurred with the next highest frequency (11%), followed by F152I and G156R (frequencies of 6.3 and 4.5%, respectively), both surpassing the frequency (2.7%) of I244T, the previously reported third most common pathogenic change. These sequencing data indicate that AGXT is even more variable than formerly believed, with 28 new variants (21 mutations and seven polymorphisms) detected, with highest frequencies on exons 1, 4, and 7. When limited to these three exons, molecular analysis sensitivity was 77%, compared with 98% for whole-gene sequencing. These are the first data in support of comprehensive AGXT analysis for the diagnosis of PH1, obviating a liver biopsy in most well-characterized patients. Also reported here is previously unavailable evidence for the pathogenic basis of all AGXT missense variants, including evolutionary conservation data in a multisequence alignment and use of a normal control population.

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J. Am. Soc. Nephrol. 2007 18: 1617-1618. [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673