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

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. 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. 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. 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.