In other species: pig , taurine cattle , indicine cattle (zebu)

Categories: Integument (skin) phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 263700 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: 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.
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: