title: 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.affiliation: Department of Clinical Biochemistry, University College London Hospitals, London, UK. emma.l.williams@uclh.nhs.uk
authors.forename: Emma L
authors.initials: EL
authors.lastname: Williams
authors.forename: Detlef
authors.initials: D
authors.lastname: Bockenhauer
authors.forename: William G
authors.initials: WG
authors.lastname: van't Hoff
authors.forename: Nikhil
authors.initials: N
authors.lastname: Johri
authors.forename: Chris
authors.initials: C
authors.lastname: Laing
authors.forename: Manish D
authors.initials: MD
authors.lastname: Sinha
authors.forename: Robert
authors.initials: R
authors.lastname: Unwin
authors.forename: Adie
authors.initials: A
authors.lastname: Viljoen
authors.forename: Gill
authors.initials: G
authors.lastname: Rumsby
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006960:Hyperoxaluria, Primary / Q000145:classification / Q000201:enzymology* / Q000235:genetics*; D007223:Infant; D008954:Models, Biological; D009154:Mutation; D020125:Mutation, Missense; D007652:Oxo-Acid-Lyases / Q000172:deficiency* / Q000235:genetics*; D022821:RNA Splice Sites; D017384:Sequence Deletion; D013141:Spiro Compounds; D055815:Young Adult
chemical_list: C529377:BAS 100; D018389:Codon, Nonsense; D022821:RNA Splice Sites; D013141:Spiro Compounds; D007652:Oxo-Acid-Lyases; C021415:4-hydroxy-2-oxoglutarate aldolase