HAO1 (hydroxyacid oxidase 1; HGNC:4809, NCBI Gene ID 54363) is a human locus mapped to chromosome band 20p12.3 that encodes peroxisomal FMN-dependent Glycolate Oxidase homotetramer (370 aa; EC 1.1.3.15). HAO1 acts in hepatic peroxisomal oxidation of glycolate to glyoxylate (upstream of oxalate synthesis), together with LDHA (Lactate Dehydrogenase A Gene), Small Interfering RNA (siRNA), and CRISPR-Cas9 Genome Editing. Encodes liver-specific peroxisomal glycolate oxidase, the validated substrate-reduction target of lumasiran siRNA in primary hyperoxaluria type 1.
Hepatic peroxisomal oxidation of glycolate to glyoxylate (upstream of oxalate synthesis)
Clinical / Therapeutic Role
Substrate-reduction therapeutic target of FDA-approved lumasiran (Oxlumo) siRNA & CRISPR editing for Primary Hyperoxaluria Type 1
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 8-exon gene on chromosome 20p12.3 encoding a 370-amino-acid flavin mononucleotide (FMN)-dependent alpha-hydroxyacid oxidase featuring a classic (beta/alpha)8 TIM-barrel fold and a C-terminal Ser-Lys-Ile peroxisomal targeting signal 1 (PTS1).
Cellular & Tissue Expression Profile: Restricted exclusively to hepatic hepatocyte peroxisomes, where it functions immediately upstream of alanine-glyoxylate aminotransferase (AGXT) and cytosolic lactate dehydrogenase A (LDHA).
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Catalyzes the O2-dependent oxidation of two-carbon glycolate into glyoxylate (generating hydrogen peroxide inside the peroxisome); in healthy hepatocytes, AGXT transaminates glyoxylate into innocuous glycine, whereas when AGXT is deficient, accumulated glyoxylate escapes into the cytosol and is oxidized by LDHA into insoluble calcium oxalate.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: While primary hyperoxaluria type 1 (PH1) is caused by biallelic loss-of-function mutations in AGXT—leading to massive hepatic oxalate overproduction, recurrent calcium oxalate nephrolithiasis, nephrocalcinosis, and end-stage renal failure—human individuals discovered through population exome sequencing to carry homozygous complete loss-of-function mutations in HAO1 exhibit harmless elevated plasma/urinary glycolate with zero clinical pathology, proving HAO1 is completely dispensable in humans.
Therapeutic & Clinical Pharmacology: Silencing HAO1 starves the toxic pathway of glyoxylate substrate: the GalNAc-conjugated siRNA lumasiran (Oxlumo, FDA-approved in 2020) degrades hepatic HAO1 mRNA to normalize urinary oxalate excretion in PH1 patients, and in vivo CRISPR-Cas9 HAO1 knockout is advancing as a single-dose curative strategy.