Yaacov Frishberg1, Avraham Zeharia2, Roman Lyakhovetsky3, Ruth Bargal3, Ruth Belostotsky3. 1. Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem, Israel The Hebrew University School of Medicine, Jerusalem, Israel. 2. Ambulatory Day Care Hospitalization Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel. 3. Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem, Israel.
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. METHODS AND 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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. METHODS AND 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Entities:
Keywords:
Clinical Genetics; Metabolic Disorders; Renal Medicine
Authors: Abigail Liebow; Xingsheng Li; Timothy Racie; Julia Hettinger; Brian R Bettencourt; Nader Najafian; Patrick Haslett; Kevin Fitzgerald; Ross P Holmes; David Erbe; William Querbes; John Knight Journal: J Am Soc Nephrol Date: 2016-07-18 Impact factor: 10.121
Authors: Xingsheng Li; John Knight; Sonia Fargue; Brianna Buchalski; Zhengrong Guan; Edward W Inscho; Abigail Liebow; Kevin Fitzgerald; William Querbes; W Todd Lowther; Ross P Holmes Journal: Biochim Biophys Acta Date: 2015-12-02