Alternative titles; symbols
HGNC Approved Gene Symbol: SUMF1
SNOMEDCT: 54898003; ICD10CM: E75.26;
Cytogenetic location: 3p26.1 Genomic coordinates (GRCh38) : 3:4,034,486-4,467,269 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p26.1 | Multiple sulfatase deficiency | 272200 | Autosomal recessive | 3 |
The SUMF1 gene encodes an enzyme required for posttranslational modification and catalytic activation of the family of sulfatase enzymes. Sulfatase enzymes catalyze the hydrolysis of sulfate esters such as glycosaminoglycans, sulfolipids, and steroid sulfates. C-alpha-formylglycine (FGly), the catalytic residue in the active site of eukaryotic sulfatases, is posttranslationally generated from a cysteine by SUMF1, the FGly-generating enzyme (FGE), in the endoplasmic reticulum (ER) (summary by Roeser et al. (2006)).
Dierks et al. (2003) purified FGE from bovine testis. By searching sequence databases and RT-PCR using fibroblast RNA, they isolated a human cDNA encoding FGE, which they designated SUMF1. The deduced 374-amino acid protein contains a 33-residue signal sequence and an N-glycosylation site, and it has a tripartite domain structure. SUMF1 is conserved in prokaryotes and eukaryotes and shares 87% and 94% amino acid identity with its mouse and rat orthologs, respectively. Northern blot analysis detected a 2.1-kb transcript in heart, brain, placenta, lung, liver, skeletal muscle, kidney, and pancreas, as well as in skin fibroblasts. Expression was highest in pancreas and kidney and lowest in brain. Immunofluorescence analysis showed colocalization of SUMF1 with a luminal protein of the ER. Western blot analysis indicated that SUMF1 has an apparent molecular mass of 42 to 44 kD.
Independently, Cosma et al. (2003) identified the SUMF1 gene by functional complementation using microcell-mediated chromosome transfer. A SUMF1 paralog, SUMF2 (607940), shares 48% amino acid identity with SUMF1. Northern blot analysis detected SUMF1 expression in all tissues tested, with highest levels in kidney and liver.
By genomic sequence analysis, Dierks et al. (2003) determined that the SUMF1 gene has 9 exons and spans 105 kb. The exon-intron structure is conserved in mouse.
By genomic sequence analysis, Dierks et al. (2003) mapped the SUMF1 gene to chromosome 3p26. They mapped the mouse Sumf1 gene to chromosome 6E2 in a region that shows homology of synteny to human chromosome 3p26.
Cosma et al. (2003) observed functional conservation of SUMF1 among distantly related species, suggesting a critical biologic role. Coexpression of SUMF1 with sulfatases resulted in a synergistic increase of enzymatic activity, indicating that SUMF1 is both an essential and a limiting factor for sulfatases. The authors concluded that these data have implications on the feasibility of enzyme replacement therapy for 8 distinct inborn errors of metabolism.
Roeser et al. (2006) stated that cys336 and cys341 within the active site are involved in the catalytic action of FGE. They examined the crystal structure of cys336-to-ser and cys341-to-ser mutants of FGE, as well as wildtype FGE modified by an SH-reactive agent or binding a peptide substrate. Their observations confirmed that the cys336/cys341 pair does not form a disulfide bond, predominantly due to the redox activity of cys336, which is fully oxidized to sulfonic acid in the wildtype enzyme. The negative potential of cys336 allows it to react with molecular oxygen as part of a novel oxygenase mechanism that does not rely on any cofactors. A substrate binding groove borders the cys336/cys341 pair, and cys341 stabilizes the substrate by forming a disulfide bond with a cysteine within the substrate peptide sequence. The binding groove requires the substrate to be elongated, providing further evidence that sulfatase modification in the ER occurs before folding.
Dierks et al. (2003) identified 9 mutations in the SUMF1 gene in 7 patients with multiple sulfatase deficiency (MSD; 272200). The activity of sulfatases was partially restored in patient fibroblasts by transduction of SUMF1-encoding cDNA, but not by cDNA carrying an MSD mutation.
Cosma et al. (2003) identified several mutations in the SUMF1 gene in 12 unrelated patients with MSD. They showed that SUMF1 was able to rescue the enzymatic deficiency in patients' cell lines.
In 20 patients with MSD of different ethnic origins, Cosma et al. (2004) performed mutation analysis of the SUMF1 gene. The clinical presentation of these patients was variable, ranging from severe neonatal forms to mild phenotypes showing mild neurologic involvement. Twenty-two SUMF1 mutations were identified, including missense, nonsense, microdeletion, and splicing mutations. All missense mutations were expressed in culture to study their ability to enhance the activity of sulfatases. In 11 cases the predicted amino acid changes resulted in severely impaired sulfatase-enhancing activity. In the case of 2 mutations, high residual activity was observed on some, but not all, of the 9 sulfatases tested, suggesting that some SUMF1 mutations may have variable effects on the activity of each sulfatase.
Schlotawa et al. (2011) observed clear genotype/phenotype correlations among 10 patients with multiple sulfatase deficiency, including 1 with neonatal onset, 7 with severe late-infantile onset, and 2 with mild late-infantile onset. The most severely affected patient with neonatal onset had marked impairments in both SUMF1 stability and enzyme activity and was compound heterozygous for a splice site and a nonsense mutation (607939.0001 and 607939.0003, respectively). Sulfatase activities in this patient were almost undetectable. In contrast, 2 patients with mild late-infantile onset were homozygous for a missense mutation (G263V; 607939.0018), which showed the highest residual enzymatic activity among the studied variants despite decreased stability. Patients with the intermediate severe late-infantile form had mutations that compromised stability and caused low levels of residual activity (see, e.g., S155P; 607939.0010).
Settembre et al. (2007) found that Sumf1-null mice displayed early mortality, congenital growth retardation, skeletal abnormalities, and neurologic deficits, similar to human patients with MSD. Massive lysosomal storage of glycosaminoglycans was observed in all tissues examined and was associated with systemic inflammation, apoptosis, and neurodegeneration. Sumf1-null mice completely lacked all sulfatase activities, indicating that mammals have a single sulfatase modification system.
In patients with multiple sulfatase deficiency (MSD; 272200), Dierks et al. (2003) and Cosma et al. (2003) identified heterozygosity for a 4-bp deletion (GTAA) at position +5 of intron 3 of the SUMF1 gene. The mutation destroyed the splice donor site of intron 3, resulting in an in-frame deletion of exon 3 (residues 149 to 173). Dierks et al. (2003) referred to the mutation as IVS3+5-8del, while Cosma et al. (2003) referred to it as 519+4delGTAA. The patient reported by Cosma et al. (2003) also had a C-to-A transversion at nucleotide 1076, resulting in a ser359-to-ter substitution (S359X; 607939.0002). The patient reported by Dierks et al. (2003) also had a C-to-T transition at nucleotide 979, resulting in an arg327-to-ter substitution (R327X; 607939.0003).
Schlotawa et al. (2011) reported a patient with severe neonatal onset of MSD who was compound heterozygous for the intron 3 mutation and R327X (607939.0003). Both mutations were predicted to be null mutations, but the splice site mutation was shown to retain about 0.3% residual activity. Patient fibroblasts showed severely reduced levels of SUMF1.
For discussion of the ser359-to-ter (S359X) mutation in the SUMF1 gene that was found in compound heterozygous state in a patient with multiple sulfatase deficiency (MSD; 272200) by Cosma et al. (2003), see 607939.0001.
For discussion of the arg327-to-ter (R327X) mutation in the SUMF1 gene that was found in compound heterozygous state in a patient with multiple sulfatase deficiency (MSD; 272200) by Dierks et al. (2003), see 607939.0001.
In patients with multiple sulfatase deficiency (MSD; 272200), Dierks et al. (2003) and Cosma et al. (2003) identified homozygosity for a C-to-T transition at nucleotide 1045 of the SUMF1 gene, resulting in the substitution of a conserved amino acid, arg349 to trp (R349W).
In patients with multiple sulfatase deficiency (MSD; 272200), Dierks et al. (2003) and Cosma et al. (2003) identified compound heterozygosity for a G-to-A transition at nucleotide 1046 of the SUMF1 gene, resulting in the substitution of a conserved amino acid, arg349 to gln (R349Q). The second mutation was a T-to-C transition at nucleotide 1006, resulting in the substitution of a conserved amino acid, cys336 to arg (C336R; 607939.0006).
For discussion of the cys336-to-arg (C336R) mutation in the SUMF1 gene that was found in compound heterozygous state in patients with multiple sulfatase deficiency (MSD; 272200) by Dierks et al. (2003) and Cosma et al. (2003), see 607939.0005.
In a patient with multiple sulfatase deficiency (MSD; 272200), Dierks et al. (2003) identified compound heterozygosity for a C-to-T transition at nucleotide 836 of the SUMF1 gene, resulting in the substitution of a conserved amino acid, ala279 to val (A279V). The second mutation was a frameshift deletion of 1 bp (C) at nucleotide 243 (607939.0008), resulting in a truncated protein.
In a patient with moderate MSD, Cosma et al. (2003) identified compound heterozygosity for the A279V mutation and a 1-bp deletion (A) at position -2 of intron 5 (603-2delA; 607939.0016), resulting in skipping of exon 5.
For discussion of the 1-bp deletion in the SUMF1 gene (243delC) that was found in compound heterozygous state in a patient with multiple sulfatase deficiency (MSD; 272200) by Dierks et al. (2003), see 607939.0007.
In a patient with severe neonatal multiple sulfatase deficiency (MSD; 272200), Dierks et al. (2003) and Cosma et al. (2003) identified heterozygosity for a frameshift deletion of 1 bp (G) at nucleotide 661 of the SUMF1 gene, resulting in a truncated protein. The second mutation in this patient, who was originally reported by Burch et al. (1986), was not identified.
In 2 patients with multiple sulfatase deficiency (MSD; 272200), Cosma et al. (2003) identified homozygosity for a T-to-C transition at nucleotide 463 of the SUMF1 gene, resulting in a ser155-to-pro substitution (S155P).
Schlotawa et al. (2011) reported 3 patients with severe late-infantile onset of MSD who were homozygous for the S155P mutation. In vitro functional expression studies in fibrosarcoma cells showed that the mutant protein had reduced expression and was unstable, but localized to the ER and retained about 1.6% residual catalytic activity compared to wildtype. The mutant protein was not secreted into the medium, indicating that it was retained inside the cell and degraded, resulted in a loss of function. Patient fibroblasts showed severely reduced levels of SUMF1.
In a patient with multiple sulfatase deficiency (MSD; 272200), Cosma et al. (2003) identified compound heterozygosity for a T-to-G transversion at nucleotide 2 of the SUMF1 gene, resulting in substitution of the initiator met codon, met1 to arg (M1R). The second mutation was a frameshift deletion of 1 bp (C) at nucleotide 276, resulting in a truncated protein (607939.0012).
For discussion of the 1-bp deletion in the SUMF1 gene (276delC) that was found in compound heterozygous state in a patient with multiple sulfatase deficiency (272200) by Cosma et al. (2003), see 607939.0011.
In 2 patients with multiple sulfatase deficiency (MSD; 272200), Cosma et al. (2003) identified a C-to-T transition at nucleotide 1033 of the SUMF1 gene, resulting in an arg345-to-cys substitution (R345C). One patient was homozygous for the R345C mutation, while the other was compound heterozygous for R345C and a G-to-A transition at nucleotide 653, resulting in a cys218-to-tyr substitution (C218Y; 607939.0015).
Schlotawa et al. (2011) reported a patient with severe late-infantile onset of MSD who was homozygous for the R345C mutation. In vitro functional expression studies in fibrosarcoma cells showed that the mutant protein had normal expression and localized correctly to the ER, but was unstable and was secreted into the medium, The mutant protein retained about 2.0% residual catalytic activity compared to wildtype. Patient fibroblasts showed severely reduced levels of SUMF1.
In a patient with multiple sulfatase deficiency (MSD; 272200), Cosma et al. (2003) identified compound heterozygosity for a G-to-C transversion at nucleotide 1042 of the SUMF1 gene, resulting in an ala348-to-pro substitution (A348P). The second mutation was an A-to-G transition at nucleotide 1, resulting in a met1-to-val substitution (M1V; 607939.0017).
For discussion of the cys218-to-tyr (C218Y) mutation in the SUMF1 gene that was found in compound heterozygous state in a patient with multiple sulfatase deficiency (272200) by Cosma et al. (2003), see 607939.0013.
For discussion of the 1-bp deletion (A) at position -2 of intron 5 in the SUMF1 gene that was found in compound heterozygous state in a patient with multiple sulfatase deficiency (MSD; 272200) by Cosma et al. (2003), see 607939.0007.
For discussion of the met1-to-val (M1V) mutation in the SUMF1 gene that was found in compound heterozygous state in a patient with multiple sulfatase deficiency (MSD; 272200) by Cosma et al. (2003), see 607939.0014.
In 2 patients with mild late-infantile onset of multiple sulfatase deficiency (MSD; 272200), Schlotawa et al. (2011) identified a homozygous 788G-T transversion in the SUMF1 gene, resulting in a gly263-to-val (G263V) substitution in a highly conserved residues. In vitro functional expression studies showed that the mutant protein was expressed, correctly localized to the ER, and was secreted. However, the mutant protein showed decreased stability and reduced activity, at about 16% compared to wildtype. Patient fibroblasts showed reduced levels of SUMF1, but there were residual activities of several sulfatases. Schlotawa et al. (2011) suggested that the milder phenotype in these patients resulted from residual enzymatic activity.
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Cosma, M. P., Pepe, S., Parenti, G., Settembre, C., Annunziata, I., Wade-Martins, R., Di Domenico, C., Di Natale, P., Mankad, A., Cox, B., Uziel, G., Mancini, G. M. S., Zammarchi, E., Donati, M. A., Kleijer, W. J., Filocamo, M., Carrozzo, R., Carella, M., Ballabio, A. Molecular and functional analysis of SUMF1 mutations in multiple sulfatase deficiency. Hum. Mutat. 23: 576-581, 2004. [PubMed: 15146462] [Full Text: https://doi.org/10.1002/humu.20040]
Dierks, T., Schmidt, B., Borissenko, L. V., Peng, J., Preusser, A., Mariappan, M., von Figura, K. Multiple sulfatase deficiency is caused by mutations in the gene encoding the human C-alpha-formylglycine generating enzyme. Cell 113: 435-444, 2003. [PubMed: 12757705] [Full Text: https://doi.org/10.1016/s0092-8674(03)00347-7]
Roeser, D., Preusser-Kunze, A., Schmidt, B., Gasow, K., Wittmann, J. G., Dierks, T., von Figura, K., Rudolph, M. G. A general binding mechanism for all human sulfatases by the formylglycine-generating enzyme. Proc. Nat. Acad. Sci. 103: 81-86, 2006. [PubMed: 16368756] [Full Text: https://doi.org/10.1073/pnas.0507592102]
Schlotawa, L., Ennemann, E. C., Radhakrishnan, K., Schmidt, B., Chakrapani, A., Christen, H.-J., Moser, H., Steinmann, B., Dierks, T., Gartner, J. SUMF1 mutations affecting stability and activity of formylglycine generating enzyme predict clinical outcome in multiple sulfatase deficiency. Europ. J. Hum. Genet. 19: 253-261, 2011. [PubMed: 21224894] [Full Text: https://doi.org/10.1038/ejhg.2010.219]
Settembre, C., Annunziata, I., Spampanato, C., Zarcone, D., Cobellis, G., Nusco, E., Zito, E., Tacchetti, C., Cosma, M. P., Ballabio, A. Systemic inflammation and neurodegeneration in a mouse model of multiple sulfatase deficiency. Proc. Nat. Acad. Sci. 104: 4506-4511, 2007. [PubMed: 17360554] [Full Text: https://doi.org/10.1073/pnas.0700382104]