Alternative titles; symbols
HGNC Approved Gene Symbol: HAO1
Cytogenetic location: 20p12.3 Genomic coordinates (GRCh38): 20:7,882,985-7,940,458 (from NCBI)
2-Hydroxyacid oxidases can oxidize a broad range of 2-hydroxyacids, ranging from glycolate to long-chain 2-hydroxy fatty acids such as 2-hydroxypalmitate. These enzymes utilize a flavin cofactor and convert 2-hydroxyacids to 2-ketoacids with the concomitant reduction of molecular oxygen to hydrogen peroxide.
The human liver-specific enzyme glycolate oxidase, or hydroxyacid oxidase-1 (HAO1), catalyzes the oxidation of glycolate to glyoxylate within the peroxisomes of heaptocytes (summary by Frishberg et al., 2014).
Kohler et al. (1999) stated that 2 isozymes of alpha-hydroxyacid oxidase, also known as glycolate oxidase (GOX; EC 1.1.3.15), had been reported in animals. One isozyme is kidney-specific and prefers long-chain alpha-hydroxyacid as substrate, whereas the other is liver-specific and prefers short-chain alpha-hydroxyacid. Using a mouse cDNA library enriched for iron-responsive elements (IRE), Kohler et al. (1999) cloned the first vertebrate hydroxyacid oxidase homolog, mouse Hao1. The full-length cDNA of Hao1 encodes a deduced 370-amino acid protein with a predicted molecular mass of 4.1 kD. The Hao1 protein contains an IRE-like sequence in the 3-prime untranslated region, with one mismatch in the predicted upper stem structure. By Northern blot analysis, Kohler et al. (1999) showed that expression of Hao1 is liver-specific. They confirmed the enzymatic activity of the Hao1 protein in a transformed bacterial assay. The mouse Hao1 protein shares over 55% and 48% amino acid identity with the plant and C. elegans GOX proteins, respectively. Kohler et al. (1999) demonstrated that although Hao1 contains an IRE-like element in the 3-prime UTR, its binding to rat iron regulatory proteins (IRP1, 100880; IRP2, 147582) is temperature-dependent and does not occur in vivo. They suggested that the A:A mismatch in the IRE-like element interferes with thermodynamically stable interaction between Hao1 and IRPs so that Hao1 does not confer iron-dependent regulation in cells.
Kohler et al. (1999) identified several human EST clones with similarity to mouse Hao1; the partial sequence derived from these clones exhibited over 87% amino acid identity with the mouse Hao1 protein.
The plant glycolate oxidase, which has an essential role in photorespiration, is a prototypic 2-hydroxyacid oxidase. By searching an EST database for human cDNAs capable of encoding proteins with sequence similarity to spinach GOX, Jones et al. (2000) identified HAO1 and HAO2 (605176); although they also reported the identification of human HAO3 (HAOX3), an erratum stated that this cDNA belonged to mouse. The predicted 370-amino acid HAO1 protein, which the authors called HAOX1, terminates in a near-consensus type 1 peroxisomal targeting signal (PTS1). Indirect immunofluorescence indicated that HAO1 localizes to the peroxisome. HAO1 shares 54.6% amino acid sequence identity with spinach GOX and 46% identity with HAO2. Recombinant HAO1 had 2-hydroxyacid oxidase activity. It was most active on the 2-carbon substrate glycolate, but was also active on 2-hydroxy fatty acids. Northern blot analysis of 16 human tissues detected an approximately 2.0-kb HAO1 transcript at a high level in liver but at a very low level in kidney, an approximately 1.2-kb HAO1 transcript at a high level in pancreas, and an approximately 2.4-kb HAO1 transcript at a very low level in placenta.
Williams et al. (2000) also cloned HAO1. They pointed out that the HAO1 protein shares 89% sequence similarity with mouse Hao1.
By genomic sequence analysis, Williams et al. (2000) determined that the HAO1 gene spans 57 kb and contains 8 exons.
Jones et al. (2000) noted that a region of the HAO1 gene matches the sequence of an STS that has been mapped to 20p. Williams et al. (2000) stated that the HAO1 gene maps to 20p12.
For discussion of a possible association between mutation in the HAO1 gene and isolated glycolic aciduria, see 605023.0001.
This variant is classified as a variant of unknown significance because its contribution to isolated glycolic aciduria has not been confirmed.
Frishberg et al. (2014) reported an 8-year-old boy, born to consanguineous parents of Arab descent, with persistent markedly increased urinary glycolic acid excretion with normal excretion of oxalate, citrate, and glycerate. Abdominal ultrasound demonstrated normal-sized kidneys without nephrocalcinosis or nephrolithiasis. By direct sequencing of the HAO1 gene, the authors identified homozygosity for a c.814-1G-C mutation, which was predicted to eliminate the splice acceptor site, thus skipping exon 6 and giving rise to an aberrant transcript and a shortened protein (272_324del). The effect of the mutation on splicing was validated by an in vitro hybrid-minigene approach. The parents were heterozygous for the mutation, which was also not found in homozygous state in his brother or 3 healthy sisters. Both the proband and his brother had previously been found to have AAMR syndrome (615510), caused by mutation in the GMPPA gene (615495.0002). The brother had normal urinary glycolic acid excretion. Frishberg et al. (2014) concluded that HAO1 deficiency in the proband is asymptomatic and unrelated to AAMR syndrome.
Frishberg, Y., Zeharia, A., Lyakhovetsky, R., Bargal, R., Belostotsky, R. Mutations in HAO1 encoding glycolate oxidase cause isolated glycolic aciduria. J. Med. Genet. 51: 526-529, 2014. [PubMed: 24996905] [Full Text: https://doi.org/10.1136/jmedgenet-2014-102529]
Jones, J. M., Morrell, J. C., Gould, S. J. Identification and characterization of HAOX1, HAOX2, and HAOX3, three human peroxisomal 2-hydroxy acid oxidases. J. Biol. Chem. 275: 12590-12597, 2000. Note: Erratum: J. Biol. Chem. 279: 35122 only, 2004. [PubMed: 10777549] [Full Text: https://doi.org/10.1074/jbc.275.17.12590]
Kohler, S. A., Menotti, E., Kuhn, L. C. Molecular cloning of mouse glycolate oxidase: high evolutionary conservation and presence of an iron-responsive element-like sequence in the mRNA. J. Biol. Chem. 274: 2401-2407, 1999. Note: Erratum: J. Biol. Chem. 274: 15966, 1999. [PubMed: 9891009] [Full Text: https://doi.org/10.1074/jbc.274.4.2401]
Williams, E., Cregeen, D., Rumsby, G. Identification and expression of a cDNA for human glycolate oxidase. Biochim. Biophys. Acta 1493: 246-248, 2000. [PubMed: 10978532] [Full Text: https://doi.org/10.1016/s0167-4781(00)00161-5]