title: Mutations in HAO1 encoding glycolate oxidase cause isolated glycolic aciduria.
abstract: BACKGROUND
  The primary hyperoxalurias are a group of recessive kidney diseases, characterised by extensive accumulation of calcium oxalate that progressively coalesces into kidney stones. Oxalate overproduction is facilitated by perturbations in the metabolism of glyoxylate, the product of glycolate oxidation, and the immediate precursor of oxalate. Glycolic aciduria associated with hyperoxaluria is regarded as the hallmark of type 1 primary hyperoxaluria. The genetic basis of isolated glycolic aciduria is reported here.
  
  
  RESULTS
  Two brothers, born to consanguineous healthy parents of Arab descent, were evaluated for psychomotor delay associated with triple-A-like syndrome (anisocoria, alacrima and achalasia). The proband showed markedly increased urinary glycolic acid excretion with normal excretion of oxalate, citrate and glycerate. Abdominal ultrasound showed normal-sized kidneys with normal echotexture. The genetic nature of triple-A-like syndrome in this kindred was found to be unrelated to this metabolic abnormality. Direct DNA sequencing of glycolate oxidase gene (HAO1) revealed a homozygous c.814-1G>C mutation in the invariant -1 position of intron 5 splice acceptor site. Since HAO1 is a liver-specific enzyme, the effect of this novel mutation on splicing was validated by an in vitro hybrid-minigene approach. We confirmed the appearance of an abnormal splice variant in cells transfected with mutant minigene vector.
  
  
  CONCLUSIONS
  Our results pinpoint the expression of defective splice variant of glycolate oxidase as the cause of isolated asymptomatic glycolic aciduria. This observation contributes to the development of novel approaches, namely, substrate reduction, for the treatment of primary hyperoxaluria type I.
authors.affiliation: Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem, Israel The Hebrew University School of Medicine, Jerusalem, Israel.
authors.forename: Yaacov
authors.initials: Y
authors.lastname: Frishberg
authors.affiliation: Ambulatory Day Care Hospitalization Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
authors.forename: Avraham
authors.initials: A
authors.lastname: Zeharia
authors.affiliation: Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Roman
authors.initials: R
authors.lastname: Lyakhovetsky
authors.affiliation: Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Bargal
authors.affiliation: Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Belostotsky
mesh_terms: D000309:Adrenal Insufficiency; D000429:Alcohol Oxidoreductases / Q000235:genetics*; D002648:Child; D004931:Esophageal Achalasia; D006016:Glycolates / Q000652:urine; D006038:Glyoxylates / Q000378:metabolism; D006801:Humans; D006959:Hyperoxaluria / Q000209:etiology / Q000235:genetics; D008297:Male; D008661:Metabolism, Inborn Errors / Q000150:complications / Q000235:genetics
chemical_list: D006016:Glycolates; D006038:Glyoxylates; C031149:glycolic acid; D000429:Alcohol Oxidoreductases; C408463:HAO1 protein, human; C031150:glyoxylic acid
keywords: Clinical Genetics; Metabolic Disorders; Renal Medicine