OMIA:001175-9685 : Porphyria, congenital erythropoietic in Felis catus
Categories: Integument (skin) phene
Possibly relevant human trait(s) and/or gene(s) (MIM number): 263700 (trait)
Links to MONDO diseases: No links.
Mendelian trait/disorder: yes
Mode of inheritance: Autosomal recessive
Considered a defect: yes
Key variant known: yes
Year key variant first reported: 2010
Cross-species summary: Porphyrins are a class of organic compounds characterised by four pyrrole nuclei connected in a ring structure. When combined with iron, porphyrins form haem, which is a component of haemoglobin, cytochromes, catalases and peroxidases. Thus, porphyrins are constituents of many compounds that play a vital role in biological systems. The biosynthesis of porphyrins involves a six-step process, starting with aminolaevulinic acid (ALA) and ending with protoporphyrin. Each step is catalysed by an enzyme. A deficiency of any one of these enzymes results in a buildup of intermediates prior to the step for which the enzyme is lacking, and a deficiency of intermediates after that step. In much of the literature, these intermediates are loosely called porphyrins. Congenital eryhtropoietic porphyria results from a deficiency of the third enzyme, uroporphyrinogen III cosynthetase, and a consequent buildup of intermediates (i.e. a buildup of porphyrins) that have been synthesised in the three previous steps.
Species-specific symbol: CEP
Species-specific description: Congenital erythropoietic porphyria (CEP) is a disorder of heme synthesis characterized by erythrodontia (brownish teeth) that fluoresce pink under UV light and reddish-brown urine. No other clinical signs were noted (Clavero et al 2010). The presenting signs are the same as those of acute intermittent porphyria (AIP) in cats. Cats with CEP are deficient in uroporphyrinogen III synthase (UROS) activity, a necessary enzyme in the heme synthesis pathway. This is a potential model for human CEP (OMIM#606938 and #263700), as the mutations occur in the same gene.
Edited by Dr. Mark Haskins
Inheritance: The mode of inheritance is autosomal recessive.
Molecular basis: By sequencing the candidate gene for this disorder (uroporphyrinogen III synthase; UROS), Clavero et al. (2010) identified two mutations for which a single affected cat was homozygous: "c.140C>T (p.S47F) in exon 3 and c.331G>A (p.G111S) in exon 6". The synergistic interaction of the two mutations caused feline CEP in the reported case (Clavero et al., 2010), a single cat having CEP, based on clinical and biochemical criteria.
Clinical features: No clinical signs except for erythrodontia (brownish discolored teeth) and reddish-brown urine. The teeth fluoresce pink under UV light. The dark red pigmented urine is not hematuria or hemoglobinuria. Complete blood counts were normal except for mild normoblastosis, basophilic stippling, and polychromasia (Clavero et al., 2010). Affected cats have normal hydroxymethylbilane (HMB) synthase activity, and greatly decreased uroporphyrinogen III synthase (UROS) activity. Urinary aminolevulinic acid (ALA) and porphobilinogen (PBG) levels are normal, while uroporphyrinogen I levels in urine and plasma are markedly increased (Clavero et al., 2010).
Pathology: In the normal heme biosynthesis pathway, UROS converts HMB to uroporphyrinogen (URO’gen) III. The causative mutations render UROS unstable, so affected cats are deficient in this enzyme. If UROS is deficient, HMB is nonenzymatically converted to a URO’gen I isomer, which then is enzymatically converted to coproporphyrinogen (COPRO’gen) I. URO’gen I and COPRO’gen I isomers accumulate, and are then oxidized to their corresponding porphyrins – uroporphyrin I (URO I) and coproporphyrin I (COPRO I). URO I and COPRO I isomers then accumulate in erythroid precursors and erythrocytes. When these cells rupture, the isomers are released into circulation and are deposited in teeth, skin, and bones, and are excreted in urine and feces. Deposition in teeth and bones causes the clinically significant discoloration. Excretion in the urine is observed as dark red pigment (Clavero et al., 2010).
Prevalence: Cats presenting with brown discolored teeth may have either CEP or AIP (OMIA ID:2942). There has so far been one genetically confirmed feline case of CEP, resulting from two concurrent mutations in the UROS gene. Neither mutation was present in 100 normal cat alleles (Clavero et al., 2010, Clavero et al., 2009).
Control: Since the mode of inheritance for CEP is autosomal recessive, and the mode of inheritance for AIP is autosomal dominant (OMIA ID:2942) testing all cats that present with CEP-like signs is recommended. Breeding of cats with either condition is discouraged.
Genetic testing: Testing for these two mutations in cats that present with a CEP-like phenotype will be helpful in distinguishing CEP cats from those that have AIP (OMIA ID:2942), which is caused by mutations in a different gene (HMB-synthase).
Breed: Domestic Shorthair.
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|UROS||uroporphyrinogen III synthase||Felis catus||D2||NC_058378.1 (81256735..81221516)||UROS||Homologene, Ensembl , NCBI gene|
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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
|OMIA Variant ID||Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Source of Genetic Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|137||Porphyria, congenital erythropoietic||UROS||missense||Naturally occurring variant||Felis_catus_9.0||D2||g.[83467845C>T;83482394G>A]||c.[140C>T;331G>A]||p.[(S47F);(G111S)]||XM_003994514.4; XP_003994563.1||2010||20485863||Genomic position in Felis_catus_9.0 provided by Joshua Khamis, Leslie Lyons and Reuben Buckley.|
Cite this entry
Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
|2021||Rodney, A.R., Buckley, R.M., Fulton, R.S., Fronick, C., Richmond, T., Helps, C.R., Pantke, P., Trent, D.J., Vernau, K.M., Munday, J.S., Lewin, A.C., Middleton, R., Lyons, L.A., Warren, W.C. :|
|A domestic cat whole exome sequencing resource for trait discovery. Sci Rep 11:7159, 2021. Pubmed reference: 33785770 . DOI: 10.1038/s41598-021-86200-7.|
|2011||Swanson, W.F., Bateman, H.L., Newsom, J., Conforti, V.A., Herrick, J.R., Lambo, C.A., Haskins, M.E., Lyons, L.A., Kittleson, M.D., Harris, S.P., Fyfe, J.C., Magarey, G.M. :|
|Propagation of multiple cat hereditary disease models following assisted reproduction with frozen semen and embryos Reproduction, Fertility and Development 24:139-140 (Abstract 55), 2011.|
|2010||Clavero, S., Bishop, DF., Giger, U., Haskins, ME., Desnick, RJ. :|
|Feline congenital erythropoietic porphyria: Two homozygous UROS missense mutations cause the enzyme deficiency and porphyrin accumulation. Mol Med 16:381-388, 2010. Pubmed reference: 20485863 . DOI: 10.2119/molmed.2010.00038.|
|1979||Calabrese, EJ. :|
|Increased sensitivity to lead -- animal model: feline porphyria. Med Hypotheses 5:649-51, 1979. Pubmed reference: 491993 .|
|1975||Giddens, W.E., Labbe, R.F., Swango, L.J., Padgett, G.A. :|
|Feline congenital erythropoietic porphyria associated with severe anemia and renal disease: clinical, morphologic, and biochemical studies American Journal of Pathology 80:367-386, 1975. Pubmed reference: 1231563 .|
|1970||Glenn, BL. :|
|Feline porphyria: Comparative aspects with porphyria of other animals and man Animal Models in Biomedical Research III. National Academy of Sciences, Washington DC :135-148, 1970.|
|1968||Glenn, BL., Glenn, HG., Omtvedt, IT. :|
|Congenital porphyria in the domestic cat (Felis catus): preliminary investigations on inheritance pattern. Am J Vet Res 29:1653-7, 1968. Pubmed reference: 5690689 .|
|1964||Tobias, G. :|
|Congenital porphyria in a cat J Am Vet Med Assoc 145:462-3, 1964. Pubmed reference: 14215379 .|
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