A novel mutation in the GRHPR gene in a Japanese patient with primary hyperoxaluria type 2.

Primary hyperoxaluria type 2 (PH2) is a rare monogenic genetic disorder with an autosomal recessive pattern of inheritance. The disease is caused by mutations in the GRHPR gene encoding the glyoxylate/hydroxypyruvate reductase enzyme [2,12]. The high urinary excretion of oxalate and L-glycerate is a characteristic biochemical feature of PH2. Pathologically, the increased plasma and urinary oxalate leads to calcium oxalate supersaturation in the collecting ducts, which causes progressive renal deposition of calcium oxalate in the kidney, in the form of urolithiasis and/or nephrocalcinosis. In severe cases, this occasionally leads to renal failure and/or systemic oxalosis. The diagnostic tools of PH2 include the measurement of urinary oxalate and L-glycerate, genotyping for mutations of the GRHPR gene, the measurement of GRHPR enzymatic activity in the blood cells [5,13] and measurement of enzymatic activity in liver tissue. None of these assays are ideal. Measurement of enzymatic activity in liver biopsy is complicated by comorbidity, measurement in blood cells requires sensitive assays not generally available. Measurement of urinary metabolites can occasionally lead to misdiagnosis. While genetic screening offers potential solutions to problems created by other methods, there are currently too few mutations described and evaluated for functional consequences to use this method for efficient diagnosis. The GRHPR gene is located in the pericentromeric region of chromosome 9 [2]. The gene has 9 exons and encodes a 328 amino acid, 36 kDa protein [2,8]. To date, 13 mutations have been identified [2–4,6,11,12]. All mutations reported lead to a loss of enzyme expression or function. The most common of all the mutations is 103delG in exon 2, which results in a frameshift and induces a premature stop at codon 45 [2]. The prevalence of this mutation in PH2 is around 40% [3,11] of all reported mutations and appears to have originated in a founder of Northern European origin [11]. However, it has not been found in any patient of Asian origin. The 103delG mutation is a candidate mutation for DNA screening especially in patients of Caucasian origin. The sensitivity of diagnosis using 103delG mutation in DNA samples from the individuals referred for PH2 was 33% [9]. We describe a Japanese patient with PH2 who suffers from recurrent urolithiasis without nephrocalcinosis. This 19 year old patient was diagnosed through biochemical urine analysis by gas chromatographymass spectrometry at 10 months of age [14]. In the current report, we provide the molecular basis of PH2 in this patient.