HGNC Approved Gene Symbol: SUOX
SNOMEDCT: 367368009; ICD10CM: E72.19;
Cytogenetic location: 12q13.2 Genomic coordinates (GRCh38) : 12:55,997,276-56,005,525 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.2 | Sulfite oxidase deficiency | 272300 | Autosomal recessive | 3 |
Sulfite oxidase (EC 1.8.3.1) is the terminal enzyme in the oxidative degradation pathway of sulfur-containing amino acids.
Garrett et al. (1995) isolated a 2.4-kb cDNA clone of sulfite oxidase from a human liver cDNA library. The deduced 488-amino acid protein has a molecular mass of approximately 52 kD and shows 88% homology to the rat protein and 67% homology to the chicken protein. Comparison of 3 sulfite oxidase sequences to several plant and fungal nitrate reductase sequences revealed a single conserved cysteine with highly conserved flanking sequences. Garrett et al. (1995) postulated that the conserved cysteine is a ligand of molybdenum in sulfite oxidase and nitrate reductase.
Kisker et al. (1997) determined the crystal structure of chicken liver sulfite oxidase, which is homologous to the human protein, at 1.9-angstrom resolution. They found that each monomer of the dimeric enzyme consists of 3 domains. At the active site, the Mo is penta-coordinated by 3 sulfur ligands, 1 oxo group, and 1 water/hydroxo. A sulfate molecule adjacent to the Mo identifies the substrate binding pocket.
Gross (2018) mapped the SUOX gene to chromosome 12q13.2 based on an alignment of the SUOX sequence (GenBank AY056018) with the genomic sequence (GRCh38).
Kisker et al. (1997) characterized 4 missense mutations in the SUOX gene (606887.0001-606887.0004) in cell lines from patients with isolated sulfite oxidase deficiency (ISOD; 272300). The crystallographic results predicted that 2 of these mutations (arg160 to gln, 606887.0001 and ala208 to asp, 606887.0002) are near the sulfate-binding site, whereas the other mutations (ser370 to tyr, 606887.0003 and gly473 to asp, 606887.0004) occur within the domain mediating dimerization.
Johnson et al. (2002) identified 12 novel mutations in the SUOX gene in patients with isolated sulfite oxidase deficiency. These included 2 frameshift mutations, 2 homozygous nonsense mutations, and 8 missense mutations.
Seidahmed et al. (2005) identified a 1-bp deletion in the SUOX gene (606887.0005) in a male infant with isolated sulfite oxidase deficiency.
By direct sequencing of the SUOX gene in a Turkish boy, born of consanguineous parents, with ISOD, Bender et al. (2019) identified a homozygous missense mutation (G362S; 606887.0006). Sulfite oxidase activity was absent in patient fibroblasts, but mutant SUOX protein expressed in E. coli had normal activity, suggesting differences between bacterial and human SUOX expression. G362S mutant apo-SUOX protein expressed in HEK293 cells had reduced stability and reduced molybdenum cofactor incorporation efficiency compared to wildtype, which provided evidence for a protein maturation defect. Patient fibroblasts treated with molybdate-containing growth media showed increased SUOX activity, suggesting that dietary treatment with molybdenum should be considered as a potential treatment in patients with ISOD and a mutation causing a protein maturation defect.
Kaczmarek et al. (2021) used a machine learning algorithm to determine the potential pathogenicity of missense mutations in the SUOX gene that were identified from the gnomAD database. Thirty-nine of these variants with the highest likelihood of pathogenicity were then functionally assessed with recombinant expression of the mutant protein in E.coli or HEK cells. Six mutations (W101G, H118Y, E197K, R217W, S427W, D512Y, Q518R) resulted in inactive sulfite oxidase and 7 mutations (D110, P119S, G121E, G130R, Y140C, R269H, Q396P, R459Q) resulted in severe reduction of sulfite oxidase activity. Based on these data combined with previously published data on pathogenic mutations in the SUOX gene, Kaczmarek et al. (2021) calculated an incidence rate for ISOD of 1 in 1,377,341 births.
In a cell line from a patient with isolated sulfite oxidase deficiency (ISOD; 272300), Kisker et al. (1997) found a G-to-A substitution at nucleotide 479 of the cDNA of liver sulfite oxidase, resulting in an arg-to-gln substitution at amino acid residue 160 (R160Q).
The R160Q mutation was identified by Garrett et al. (1998) in a 5-year-old girl with sulfite oxidase deficiency born of first-cousin parents of Dutch descent. Recombinant protein containing the R160Q mutation, expressed in Escherichia coli, contained its full complement of molybdenum and heme, but exhibited 2% of native activity under standard assay conditions. Absorption spectroscopy of the isolated molybdenum domains of native sulfite oxidase and of the R160Q mutant showed significant differences in the 480- and 350-nm absorption bands, suggestive of altered geometry at the molybdenum center. Other studies led to the proposal that under normal circumstances arg160 attracts the anionic substrate sulfite to the binding site near the molybdenum.
In a cell line from a patient with isolated sulfite oxidase deficiency (ISOD; 272300), Kisker et al. (1997) found a C-to-A substitution at nucleotide 623 of the cDNA of liver sulfite oxidase, resulting in an ala-to-asp substitution at amino acid 208.
In a cell line from a patient with isolated sulfite oxidase deficiency (ISOD; 272300), Kisker et al. (1997) found a G-to-A substitution at nucleotide 1109 of the cDNA of liver sulfite oxidase, resulting in a ser-to-tyr substitution at amino acid 370.
In a cell line from a patient with isolated sulfite oxidase deficiency (ISOD; 272300), Kisker et al. (1997) found a G-to-A substitution at nucleotide 1418 of the cDNA of liver sulfite oxidase, resulting in a gly-to-asp substitution at amino acid 473.
In a male infant with isolated sulfite oxidase deficiency (ISOD; 272300) from a consanguineous Arab family, Seidahmed et al. (2005) identified homozygosity for a 1-bp deletion (1244delG) in the SUOX gene, predicting a frameshift at amino acid 117 and resulting in a mutant protein of only 128 amino acids with total truncation of the molybdopterin and dimerizing domains. The parents and 1 unaffected sib were heterozygous for the deletion.
In a Turkish boy, born to consanguineous parents, with isolated sulfite oxidase deficiency (ISOD; 272300), Bender et al. (2019) identified homozygosity for a c.1084G-A transition (c.1084G-A, NM_000456.2) in the SUOX gene, resulting in a gly362-to-ser (G362S) substitution at a highly conserved residue. The mutation was identified by direct gene sequencing. Sulfite oxidase activity in patient fibroblasts was absent. Apo-SUOX protein with the G362S mutation expressed in HEK293 cells had reduced stability and reduced molybdenum cofactor incorporation efficiency, which provided evidence for a protein maturation defect.
Bender, D., Kaczmarek, A. T., Santamaria-Araujo, J. A., Stueve, B., Waltz, S., Bartsch, D., Kurian, L., Cirak, S., Schwarz, G. Impaired mitochondrial maturation of sulfite oxidase in a patient with severe sulfite oxidase deficiency. Hum. Molec. Genet. 28: 2885-2899, 2019. [PubMed: 31127934] [Full Text: https://doi.org/10.1093/hmg/ddz109]
Garrett, R. M., Bellissimo, D. B., Rajagopalan, K. V. Molecular cloning of human liver sulfite oxidase. Biochim. Biophys. Acta 1262: 147-149, 1995. [PubMed: 7599189] [Full Text: https://doi.org/10.1016/0167-4781(95)00068-r]
Garrett, R. M., Johnson, J. L., Graf, T. N., Feigenbaum, A., Rajagopalan, K. V. Human sulfite oxidase R160Q: identification of the mutation in a sulfite oxidase-deficient patient and expression and characterization of the mutant enzyme. Proc. Nat. Acad. Sci. 95: 6394-6398, 1998. [PubMed: 9600976] [Full Text: https://doi.org/10.1073/pnas.95.11.6394]
Gross, M. B. Personal Communication. Baltimore, Md. 2/1/2018.
Johnson, J. L., Coyne, K. E., Garrett, R. M., Zabot, M.-T., Dorche, C., Kisker, C., Rajagopalan, K. V. Isolated sulfite oxidase deficiency: identification of 12 novel SUOX mutations in 10 patients.(Abstract) Hum. Mutat. 20: 74 only, 2002.
Kaczmarek, A. T., Bahlmann, N., thaqi, B., May, P., Schwarz, G. Machine learning-based identification and characterization of 15 novel pathogenic SUOX missense mutations. Molec. Genet. Metab. 134: 188-194, 2021. [PubMed: 34420858] [Full Text: https://doi.org/10.1016/j.ymgme.2021.07.011]
Kisker, C., Schindelin, H., Pacheco, A., Wehbi, W. A., Garrett, R. M., Rajagopalan, K. V., Enemark, J. H., Rees, D. C. Molecular basis of sulfite oxidase deficiency from the structure of sulfite oxidase. Cell 91: 973-983, 1997. [PubMed: 9428520] [Full Text: https://doi.org/10.1016/s0092-8674(00)80488-2]
Seidahmed, M. Z., Alyamani, E. A., Rashed, M. S., Saadallah, A. A., Abdelbasit, O. B., Shaheed, M. M., Rasheed, A., Hamid, F. A., Sabry, M. A. Total truncation of the molybdopterin/dimerization domains of SUOX protein in an Arab family with isolated sulfite oxidase deficiency. Am. J. Med. Genet. 136A: 205-209, 2005. [PubMed: 15952210] [Full Text: https://doi.org/10.1002/ajmg.a.30796]