The enzyme 4-hydroxy-2-oxoglutarate aldolase is deficient in primary hyperoxaluria type 3.

Abstract

BACKGROUND:

Mutations in the 4-hydroxy-2-oxoglutarate aldolase (HOGA1) gene have been recently identified in patients with atypical primary hyperoxaluria (PH). However, it was not clearly established whether these mutations caused disease via loss of function or activation of the gene product.

METHODS:

Whole-gene sequencing of HOGA1 was conducted in 28 unrelated patients with a high clinical suspicion of PH and in whom Types 1 and 2 had been excluded.

RESULTS:

Fifteen patients were homozygous or compound heterozygous for mutations in HOGA1. In total, seven different mutations were identified including three novel changes: a missense mutation, c.107C > T (p.Ala36Val), and two nonsense mutations c.117C > A (p.Tyr39X) and c.208C > T (p.Arg70X) as well as the previously documented c.860G > T (p.Gly297Val), c.907C > T (p.Arg303Cys) and in-frame c.944_946delAGG (p.Glu315del) mutations. The recurrent c.700 + 5G > T splice site mutation in intron 5 was most common with a frequency of 67%. Expression studies on hepatic messenger RNA demonstrated the pathogenicity of this mutation.

CONCLUSIONS:

The detection of a patient with two novel nonsense mutations within exon 1 of the gene, c.117C > A (p.Tyr39X) and c.208C > T (p.Arg70X), provides definitive proof that PH Type 3 is due to deficiency of the 4-hydroxy-2-oxoglutarate aldolase enzyme.

• Authors: Emma L Williams, Detlef Bockenhauer, William G van't Hoff, Nikhil Johri, Chris Laing, Manish D Sinha, Robert Unwin, Adie Viljoen, Gill Rumsby
• Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association (Nephrol Dial Transplant) Vol. 27 Issue 8 Pg. 3191-5 (Aug 2012) ISSN: 1460-2385 [Electronic] England
• PMID: 22391140 (Publication Type: Journal Article)

Chemical References

• BAS 100
• Codon, Nonsense
• RNA Splice Sites
• Spiro Compounds
• Oxo-Acid-Lyases
• 4-hydroxy-2-oxoglutarate aldolase

Topics

• Adult
• Child
• Child, Preschool
• Codon, Nonsense
• DNA Mutational Analysis
• Heterozygote
• Homozygote
• Humans
• Hyperoxaluria, Primary (classification, enzymology, genetics)
• Infant
• Models, Biological
• Mutation
• Mutation, Missense
• Oxo-Acid-Lyases (deficiency, genetics)
• RNA Splice Sites
• Sequence Deletion
• Spiro Compounds
• Young Adult