title: Primary hyperoxaluria type 1: update and additional mutation analysis of the AGXT gene.
abstract: Primary hyperoxaluria type 1 (PH1) is an autosomal recessive, inherited disorder of glyoxylate metabolism arising from a deficiency of the alanine:glyoxylate aminotransferase (AGT) enzyme, encoded by the AGXT gene. The disease is manifested by excessive endogenous oxalate production, which leads to impaired renal function and associated morbidity. At least 146 mutations have now been described, 50 of which are newly reported here. The mutations, which occur along the length of the AGXT gene, are predominantly single-nucleotide substitutions (75%), 73 are missense, 19 nonsense, and 18 splice mutations; but 36 major and minor deletions and insertions are also included. There is little association of mutation with ethnicity, the most obvious exception being the p.Ile244Thr mutation, which appears to have North African/Spanish origins. A common, polymorphic variant encoding leucine at codon 11, the so-called minor allele, has significantly lower catalytic activity in vitro, and has a higher frequency in PH1 compared to the rest of the population. This polymorphism influences enzyme targeting in the presence of the most common Gly170Arg mutation and potentiates the effect of several other pathological sequence variants. This review discusses the spectrum of AGXT mutations and polymorphisms, their clinical significance, and their diagnostic relevance.
authors.affiliation: Clinical Biochemistry, University College London (UCL) Hospitals National Health Service (NHS) Trust, London, UK.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Williams
authors.forename: Cecile
authors.initials: C
authors.lastname: Acquaviva
authors.forename: Antonio
authors.initials: A
authors.lastname: Amoroso
authors.forename: Francoise
authors.initials: F
authors.lastname: Chevalier
authors.forename: Marion
authors.initials: M
authors.lastname: Coulter-Mackie
authors.forename: Carla G
authors.initials: CG
authors.lastname: Monico
authors.forename: Daniela
authors.initials: D
authors.lastname: Giachino
authors.forename: Tricia
authors.initials: T
authors.lastname: Owen
authors.forename: Angela
authors.initials: A
authors.lastname: Robbiano
authors.forename: Eduardo
authors.initials: E
authors.lastname: Salido
authors.forename: Hans
authors.initials: H
authors.lastname: Waterham
authors.forename: Gill
authors.initials: G
authors.lastname: Rumsby
mesh_terms: D000483:Alleles; D000818:Animals; D004252:DNA Mutational Analysis; D006801:Humans; D006960:Hyperoxaluria, Primary / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics*; D011110:Polymorphism, Genetic; D000637:Transaminases / Q000737:chemistry / Q000235:genetics*; D024182:Uniparental Disomy / Q000235:genetics
chemical_list: D000637:Transaminases; C019635:Alanine-glyoxylate transaminase