Submission Details

The gene UROS has been definitively associated with the gene-disease relationship of UROS-related porphyria also known as congenital erythropoietic porphyria (CEP) according to the gene-disease validity curation process (Standard Operating Procedures Version 11) of the ACMG.

UROS (uroporphyrinogen-III synthase) is a cytosolic enzyme and the fourth step in the heme synthesis pathway. It catalyzes the cyclization of the linear substrate hydroxymethylbilane into uroporphyrinogen III. When UROS activity is reduced, hydroxymethylbilane can spontaneously cyclize into uroporphyrinogen I isomers. Although these isomers, like uroporphyrinogen III, are substrates for the next enzyme in the pathway, UROD (Uroporphyrinogen decarboxylase), the products, coproporphyrinogen I isomers are not a substrate for the subsequent enzyme, CPOX (coproporphyrinogen-III oxidase), in heme synthesis. As a result, the non enzymatically produced uroporphyrinogen I isomers represent a dead end in the pathway (PMID: 19268002).

UROS-related porphyria, like other porphyrias, shows phenotypic variability ranging from mild to severe, with the severity generally correlating with the degree of reduced enzymatic activity. But unlike the semidominant porphyria, PPOX-related variegate porphyria where severe symptoms present at <25% WT enzyme activity, autosomal recessive UROS-related porphyria must have homozygous or biallelic mutations that nearly abolish enzyme function <5% before severe disease manifests. Mutations causing this disease are found throughout the UROS exons and in the promoter region. A common severe presentation is caused by homozygosity for the p.C73R mutation, resulting in less than 1-2% enzymatic activity (PMID: 19268002). Affected individuals may present in utero with non-immune hydrops fetalis due to hemolytic anemia. If they survive infancy, they experience extreme photosensitivity, often leading to disfigurement from severe scarring. Hemolysis is common, and additional described symptoms include red-wine-colored urine, erythrodontia (red-brown-stained teeth), splenomegaly, scleromalacia, and chronic ulcerative keratitis. Biochemical phenotypes include elevated urinary porphyrins (particularly massive amounts of uroporphyrin I), fecal porphyrins, and plasma porphyrins. In the blood, erythrocytes show polychromasia, poikilocytosis, anisocytosis, and basophilic stippling, along with an increase in reticulocytes and nucleated red blood cells. The only known cure for severe disease is bone marrow transplantation which is required as early as possible after birth, to improve chances of its effectiveness (PMID: 30594473, PMID: 31326287).

For biallelic heterozygotes if enzyme activity is <5%, severe disease often results, but for activity levels between 5-12% of WT mild to moderate disease occurs. Mild to moderate disease may have later onset and symptoms are usually cutaneous photosensitivity which often presents as bullous skin lesions, hypo- or hyperpigmentation of the affected skin, and recurrent skin infections (PMID: 19268002).

Summary of Case Level Data (12 points): 14 probands were scored with 15 unique variants (two splicing mutations, three promoter mutations and ten missense variants in exons). All of the variants scored have been characterized in E. coli for their relative enzymatic activity compared to WT.

Summary of Experimental Evidence (2.5 points): Biochemical characterization of the enzymatic reaction was scored (.5 pts). A knock-in mouse model for the P248Q missense mutation reproducing the phenotypes of erythrodontia, moderate photosensitivity, hepatosplenomegaly, and hemolytic anemia was scored at 2 points.

In summary, UROS has been definitively associated with autosomal recessive UROS-related porphyria.