title: Primary hyperoxaluria type III gene HOGA1 (formerly DHDPSL) as a possible risk factor for idiopathic calcium oxalate urolithiasis.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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-of-function 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.
authors: Mayo Clinic Hyperoxaluria Center, Divisions of Nephrology and Hypertension, and Biomedical Statisticsand Informatics, MayoClinic, Rochester, Minnesota, USA. monico.carla@mayo.edu
authors: Carla G
authors: CG
authors: Monico
authors: Sandro
authors: S
authors: Rossetti
authors: Ruth
authors: R
authors: Belostotsky
authors: Andrea G
authors: AG
authors: Cogal
authors: Regina M
authors: RM
authors: Herges
authors: Barbara M
authors: BM
authors: Seide
authors: Julie B
authors: JB
authors: Olson
authors: Eric J
authors: EJ
authors: Bergstrahl
authors: Hugh J
authors: HJ
authors: Williams
authors: William E
authors: WE
authors: Haley
authors: Yaacov
authors: Y
authors: Frishberg
authors: Dawn S
authors: DS
authors: Milliner
mesh_terms: D002129:Calcium Oxalate / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D006801:Humans; D006960:Hyperoxaluria, Primary / Q000235:genetics*; D009154:Mutation; D007652:Oxo-Acid-Lyases / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D052878:Urolithiasis / Q000209:etiology* / Q000235:genetics
chemical_list: D002129:Calcium Oxalate; D007652:Oxo-Acid-Lyases; C021415:4-hydroxy-2-oxoglutarate aldolase