Alternative titles; symbols
HGNC Approved Gene Symbol: UROS
SNOMEDCT: 190913009, 22935002; ICD10CM: E80.0;
Cytogenetic location: 10q26.2 Genomic coordinates (GRCh38) : 10:125,784,980-125,823,258 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q26.2 | Porphyria, congenital erythropoietic | 263700 | Autosomal recessive | 3 |
Uroporphyrinogen III synthase is also known as hydroxymethylbilane hydrolyase (cyclizing) (EC 4.2.1.75). It is the fourth enzyme in the 8-enzyme pathway in the conversion of glycine and succinyl-CoA to heme. It is responsible for the conversion of the linear tetrapyrrole, hydroxymethylbilane, to the cyclic tetrapyrrole, uroporphyrinogen III (Tsai et al., 1988).
Tsai et al. (1988) cloned a full-length cDNA encoding uroporphyrinogen III synthase by screening a human adult liver cDNA library. The sequence encoded a 265-amino acid protein with a molecular mass of 28,607 Da. By Northern blot, 5-prime RACE, and multiple-tissue array analyses, Aizencang et al. (2000) demonstrated the presence of 2 UROS transcripts: an erythroid-specific transcript and a housekeeping transcript, which was present at low levels in all 76 tissues tested, with highest abundance in skeletal and heart muscle and in the caudate nucleus and amygdala.
Aizencang et al. (2000) determined the structure of the 34-kb UROS gene. It contains alternative erythroid-specific and housekeeping promoters and a coding sequence comprising 9 exons.
Meng et al. (2003) determined that the 5-prime end of the UROS gene abuts the BCCIP gene (611883) on the opposite strand in a head-to-head manner. BCCIP and UROS share a functional intergenic bidirectional promoter that contains binding sites for various transcription factors.
Using cloned cDNA, Astrin et al. (1991) mapped the UROS gene to 10q25.2-q26.3. The assignment to chromosome 10 was also found when UROS sequences were specifically amplified by PCR from genomic DNA from independent panels of human-rodent somatic cell hybrids; there was 100% concordance for the presence of the human UROS PCR product and human chromosome 10.
Xu et al. (1995) cloned the mouse gene and mapped it to chromosome 7 in a region of conserved synteny with human chromosome 10.
In a patient with Gunther disease (CEP; 263700), Deybach et al. (1990) and Warner et al. (1990) identified a mutation in codon 73 of the uroporphyrinogen III synthase gene (606938.0001). Xu et al. (1995) used a rapid sequencing technique to analyze all 10 exons of the UROS gene from 20 unrelated patients with congenital erythropoietic porphyria. Of the 14 mutations identified, 10 were new. The new mutations included 6 missense mutations, a nonsense mutation, a frameshift mutation, and 2 splicing mutations.
Xu et al. (1996) stated that 17 mutations in the UROS gene had been reported as the basis of CEP: 11 missense, 1 nonsense, 2 mRNA splicing defects, 1 deletion, and 2 coding region insertions. With the exception of C73R (606938.0001) and L4F (606938.0006) which occurred in 29.6% and 9.3% of the 54 mutant alleles studied, respectively, most mutations had been identified in 1 or a few unrelated families. Analyses had revealed only 83% of the causative mutations. The V82F (606938.0009) mutation, resulting from a G-to-T transversion of the last nucleotide of exon 4, caused both a missense mutation and an aberrantly spliced RNA transcript. Prokaryotic expression of the mutant UROS alleles identified those with significant residual activity, thereby permitting genotype/phenotype predictions in this clinically heterogeneous disorder.
Shady et al. (2002) identified 8 novel mutations in the UROS gene in cases of CEP. Expression studies in E. coli showed that only 1 of the 4 novel missense mutations identified, glu81 to asp (E81D; 606938.0011), expressed significant enzymatic activity (30% of expressed wildtype activity), which was thermolabile. In addition, RT-PCR studies demonstrated that E81D, which altered the penultimate nucleotide in exon 4, impaired splicing and caused approximately 85% exon 4 skipping. The phenotype in 7 probands studied varied from mild, cutaneous only, to severe, transfusion-dependent.
In a mutation analysis of 40 unrelated patients with CEP, Desnick et al. (1998) identified both UROS mutant alleles in 29 patients and only 1 of the mutant alleles in 11 patients (11 unidentified mutations in 80 alleles, or 13.8%). Solis et al. (2001) sequenced the erythroid-specific promoter of the UROS gene in 6 patients with a single previously undefined allele and identified 4 novel mutations clustered in a 20-bp region: a -70T-C transition (606938.0013) in a putative GATA1 consensus binding element; a -76G-A transition (606938.0014); a -86C-A transversion (606938.0015) in 3 unrelated patients; and a -90C-A transversion (606938.0016) in a putative CP2 binding motif. They inserted these mutant sequences into luciferase reporter constructs. When transfected into K562 erythroid cells, these constructs yielded greatly reduced reporter activity as compared with the wildtype promoter. Electrophoretic mobility shift assays indicated that the -70T-C transition altered GATA1 binding, whereas the adjacent -76G-A transition did not. Similarly, the -90C-A transversion altered CP2 binding, whereas the -86C-A transversion did not. Thus, these 4 pathogenic erythroid promoter mutations impaired erythroid-specific transcription, caused CEP, and identified functionally important GATA1 and CP2 transcriptional binding elements for erythroid-specific heme biosynthesis.
Ged et al. (2006) stated that knockout of the Uros gene in mice results in nonviable blastocysts. By gene targeting, they developed a knockin model that reproduced the human pro248-to-gln (P248Q; 606938.0020) mutation, which leads to severe UROS deficiency. Heterozygous mice appeared normal, but homozygous mutant mice were hypotrophic at birth and produced red urine and showed erythrodontia in the first weeks of life. Homozygous mutant mice also showed photosensitivity and hepatosplenomegaly, and uroporphyrin (99% type I isomer) accumulated in urine. Total porphyrins were increased in erythrocytes and feces, while Uros enzymatic activity was below 1% of the normal level in tissues analyzed, closely mimicking CEP in humans.
In a patient with Gunther disease (CEP; 263700), Deybach et al. (1990) found heterozygosity for a T-to-C change in codon 73 (cysteine to arginine; C73R) and a C-to-T change in codon 53 (proline to leucine, or P53L; 606938.0002). Warner et al. (1990) likewise demonstrated the C73R mutation. Warner et al. (1992) found this mutation in 8 of 21 unrelated CEP patients (21% of CEP alleles). Boulechfar et al. (1992) concluded that the C73R mutation is the most frequent one found in CEP.
According to Tanigawa et al. (1995), the C73R mutation accounts for over 40% of all mutant UROS alleles in CEP. Frank et al. (1998) investigated 3 separate families with CEP from different ethnic backgrounds. Haplotype analysis using 2 microsatellite markers that closely flank the UROS gene on 10q24, spanning a region of 4 cM, showed that the C73R mutation occurred on different haplotypes in all 4 disease chromosomes studied. The results were considered consistent with the hypothesis that C73R is a hotspot mutation for CEP, and does not represent wide dispersion of a single ancestral mutant C73R allele.
Fortian et al. (2011) found that the C73R mutation destabilized the UROIIIS protein via irreversible unfolding and aggregation, followed by proteasomal degradation. At physiologic temperature, wildtype UROIIIS had a half-life of 2.5 days, whereas the C73R mutant protein had a half-life of 15 minutes. Treatment of cells with a proteasome inhibitor restored mutant protein levels, and the restored mutant protein showed 50% of wildtype enzymatic activity.
In a patient with Gunther disease (CEP; 263700), Deybach et al. (1990) found homozygosity for the pro53-to-leu mutation (P53L) in the UROS gene that was found in another patient in a genetic compound; see 606938.0001.
In a patient with congenital erythropoietic porphyria (CEP; 263700), Warner et al. (1990, 1992) demonstrated a 197C-T transition in the UROS gene, resulting in a substitution of valine for alanine at position 66. The patient was a compound heterozygote for this and the cys73-to-arg mutation (C73R; 606938.0001).
In a patient with congenital erythropoietic porphyria (CEP; 263700), Warner et al. (1992) found a 184A-G transition in the UROS gene that predicted a thr62-to-ala (T62A) substitution.
In a patient with congenital erythropoietic porphyria (CEP; 263700), Warner et al. (1992) demonstrated a 683C-T transition in the UROS gene that resulted in a thr228-to-met (T228M) substitution. Warner et al. (1992) performed genotype-phenotype correlations: the A66V/C73R, T228M/C73R, and C73R/C73R genotypes were associated with mild, moderately severe, and severe disease, respectively. Boulechfar et al. (1992) also identified this mutation.
In a patient with congenital erythropoietic porphyria (CEP; 263700), Boulechfar et al. (1992) identified a C-to-T transition at nucleotide 10 of the UROS gene, resulting in substitution of phenylalanine for leucine-4 (L4F).
In a patient with congenital erythropoietic porphyria (CEP; 263700), Boulechfar et al. (1992) demonstrated deletion of nucleotides 148-245 in the UROS gene. The deleted segment included the sites of 2 previously described point mutations, pro53-to-leu (P53L; 606938.0002) and cys73-to-arg (C73R; 606938.0001).
In a patient with congenital erythropoietic porphyria (CEP; 263700), Boulechfar et al. (1992) identified an 80-bp insertion in the UROS gene that created a frameshift at codon 221, leading to a new sequence of 45 amino acids at the C-terminal part of the protein.
In a patient with congenital erythropoietic porphyria (CEP; 263700), Xu et al. (1995) found a val82-to-phe (V82F) missense mutation in the UROS gene. The mutation occurred adjacent to the 5-prime donor site of intron 4 and resulted in approximately 54% aberrantly spliced transcripts with exon 4 deleted. Thus, this novel exonic single-base substitution caused 2 lesions: an amino acid substitution and an aberrantly spliced transcript. The mutation causing V82F is a G-to-T transversion of the last nucleotide of exon 4.
In an 18-month-old female with congenital erythropoietic porphyria (CEP; 263700), Tezcan et al. (1998) identified a G-to-A transition at nucleotide 562 in the UROS gene, predicting a gly188-to-arg (G188R) substitution. Both parents were found to be carriers of the mutation.
In an Indian patient with mild, cutaneous-only congenital erythropoietic porphyria (CEP; 263700), the offspring of nonconsanguineous parents, Shady et al. (2002) found compound heterozygosity for glu81-to-asp (E81D) and gly188-to-trp (G188W; 606938.0012) mutations in the UROS gene. The E81D mutation resulted from a 243A-T transversion. The G188W mutation resulted from a 562G-T transversion in exon 9, which predicted the substitution of a larger, hydrophobic tryptophan for an uncharged glycine. The same codon is involved in the G188R mutation (606938.0010).
For discussion of the gly188-to-trp (G188W) mutation in the UROS gene that was found in a patient with mild, cutaneous-only congenital erythropoietic porphyria (CEP; 263700) by Shady et al. (2002), see 606938.0011.
In a French male fetus with congenital erythropoietic porphyria (CEP; 263700) and nonimmune hydrops fetalis (CEP; 236750), Solis et al. (2001) identified compound heterozygosity for 2 mutations in the UROS gene: a -70T-C transition in the erythroid promoter and C73R (606938.0001). In addition, they identified heterozygosity for a -224T-C transition, which was present in approximately 4% of 200 unrelated Caucasian alleles. The healthy father was heterozygous for the -70T-C mutation and homozygous for the -224C polymorphism.
In a 49-year-old American male with mild, cutaneous-only congenital erythropoietic porphyria (CEP; 263700), Solis et al. (2001) identified compound heterozygosity for 2 mutations in the UROS gene: a -76G-A transition in the erythroid promoter and C73R (606938.0001).
In 3 unrelated patients with mild, cutaneous-only congenital erythropoietic porphyria (263700), Solis et al. (2001) identified compound heterozygosity for 2 mutations in the UROS gene: a -86C-A transversion in the erythroid promoter and a second allele, which was different in each patient. The second allele was a C73R mutation (606938.0001) in a 19-year-old Scandinavian female, a donor splice site at intron 2 (606938.0018) in a 60-year-old Scandinavian female originally studied by Xu et al. (1995), and a 1-bp insertion, 398insG (606938.0019), in a 44-year-old English male.
In a 33-year-old English male with moderately severe transfusion-dependent congenital erythropoietic porphyria (CEP; 263700), Solis et al. (2001) identified compound heterozygosity for 2 mutations in the UROS gene: a -90C-A transversion in the erythroid promoter and G225S (606938.0017).
For discussion of the gly225-to-ser (G225S) mutation in the UROS gene that was found in compound heterozygous state in a patient with congenital erythropoietic porphyria (CEP; 263700) by Solis et al. (2001), see 606938.0016.
For discussion of the splice site mutation in the UROS gene that was found in compound heterozygous state in a patient with congenital erythropoietic porphyria (CEP; 263700) by Xu et al. (1995) and Solis et al. (2001), see 606938.0015.
For discussion of the 1-bp insertion in the UROS gene (398insG) that was found in compound heterozygous state in a patient with congenital erythropoietic porphyria (CEP; 263700) by Solis et al. (2001), see 606938.0015.
Fontanellas et al. (1996) identified a C-to-A transversion at nucleotide 743 in exon 10 of the UROS gene, resulting in a pro248-to-gln (P248Q) substitution, in 3 patients from 2 Spanish families with severe congenital erythropoietic porphyria (CEP; 263700). All 3 patients also carried the cys73-to-arg mutation (C73R; 606938.0001).
In 3 unrelated patients with congenital erythropoietic porphyria (CEP; 263700), Bishop et al. (2010) identified a homozygous T-to-G transversion in intron 9 of the UROS gene 31 bp upstream from exon 10 (661-31T-G). The mutation was not found in 100 control alleles. The mutation resulted in the generation of several alternatively spliced longer transcripts containing excess nucleotides from intron 9, including one or more sequences of 81, 165, or 277 bp. The 81-bp insertion was in-frame and resulted in a functional transcript that contributed only about 0.2% residual activity, whereas the other alternative transcripts resulted in premature termination. RT-PCR of patient lymphoblasts showed about 10% normal 1.5-kb transcript with 27% abnormal transcript, and residual UROS activity was about 14%. Two of the patients were men of Ashkenazi descent. One was severely affected from birth with marked photosensitivity, hepatosplenomegaly, and anemia. The other required red cell transfusions, but had significant periods during adolescence without treatment. He had marked cutaneous involvement resulting from unprotected exposure to sunlight. The third patient was a 44-year-old man of Lebanese descent whose parents were consanguineous. He had had chronic, progressive skin ulcerations since adolescence that eventually disfigured his sun-exposed face and hands; he also had anemia. All patients had markedly elevated levels of uroporphyrin I in the urine.
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