Primary hyperoxaluria type III gene HOGA1 (Formerly DHDPSL) as a possible risk factor for idiopathic calcium oxalate urolithiasis

Carla G. Monico, Sandro Rossetti, Ruth Belostotsky, Andrea G. Cogal, Regina M. Herges, Barbara M. Seide, Julie B. Olson, Eric J. Bergstrahl, Hugh J. Williams, William E. Haley, Yaacov Frishberg, Dawn S. Milliner

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75 Scopus citations

Abstract

Background and objectives: Primary hyperoxaluria types I and II (PHI and PHII) are rare monogenic causes of hyperoxaluria and calcium oxalate urolithiasis. Recently, we described type III, due to mutations in HOGA1 (formerly DHDPSL), hypothesized to cause a gain of mitochondrial 4-hydroxy-2-oxoglutarate aldolase activity, resulting in excess oxalate. Design, setting, participants, & measurements: To further explore the pathophysiology of HOGA1, we screened additional non-PHI-PHII patients and performed reverse transcription PCR analysis. Postulating that HOGA1 may influence urine oxalate, we also screened 100 idiopathic calcium oxalate stone formers. Results Of 28 unrelated hyperoxaluric patients with marked hyperoxaluria not due to PHI, PHII, or any identifiable secondary cause, we identified 10 (36%) with two HOGA1 mutations (four novel, including a nonsense variant). Reverse transcription PCR of the stop codon and two common mutations showed stable expression. From the new and our previously described PHIII cohort, 25 patients were identified for study. Urine oxalate was lower and urine calcium and uric acid were higher when compared with PHI and PHII. After 7.2 years median follow-up, mean eGFR was 116 ml/min per 1.73 m 2. HOGA1 heterozygosity was found in two patients with mild hyperoxaluria and in three of 100 idiopathic calcium oxalate stone formers. No HOGA1 variants were detected in 166 controls. Conclusions: These findings, in the context of autosomal recessive inheritance for PHIII, support a loss-offunction mechanism for HOGA1, with potential for a dominant-negative effect. Detection of HOGA1 variants in idiopathic calcium oxalate urolithiasis also suggests HOGA1 may be a predisposing factor for this condition.

Original languageEnglish (US)
Pages (from-to)2289-2295
Number of pages7
JournalClinical Journal of the American Society of Nephrology
Volume6
Issue number9
DOIs
StatePublished - Sep 1 2011

ASJC Scopus subject areas

  • Epidemiology
  • Critical Care and Intensive Care Medicine
  • Nephrology
  • Transplantation

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    Monico, C. G., Rossetti, S., Belostotsky, R., Cogal, A. G., Herges, R. M., Seide, B. M., Olson, J. B., Bergstrahl, E. J., Williams, H. J., Haley, W. E., Frishberg, Y., & Milliner, D. S. (2011). Primary hyperoxaluria type III gene HOGA1 (Formerly DHDPSL) as a possible risk factor for idiopathic calcium oxalate urolithiasis. Clinical Journal of the American Society of Nephrology, 6(9), 2289-2295. https://doi.org/10.2215/CJN.02760311