OMIA 001493-9685 : Porphyria, acute intermittent in Felis catus
Edited by Dr. Mark HaskinsInheritance: The mode of inheritance is typically autosomal dominant. However, one mutation causes autosomal recessive AIP (see Molecular section). Molecular basis: By sequencing the two obvious comparative candidate genes (UROS and HMBS) in affected cats from four unrelated populations, Clavero et al. (2010) identified four different causative mutations in HMBS (one in each population):
1. a 3 bp deletion in exon 14 (c.842_844delGAG)
2. a T duplication in exon 5 causing a frameshift and protein truncation (c.189dupT)
3. a C to T transition in exon 9 (c.445C>T; p.R149W)
4. a G to A transition in exon 6 (c.250G>A; p.A84T) (autosomal recessive, most likely because the mutant allele encodes "a stable enzyme with ∼35% of wild-type activity" (compared with mutations 2 and 3 above, which encode "mutant enzymes with <1% wild-type activity".
Two new HMBS mutations were identified by Clavero et al. (2013): "one cat had a deletion (c.107_110delACAG) and one cat had a splicing alteration (c.826-1G>A), both leading to premature stop codons and truncated proteins (p.D36Vfs6 and p.L276Efs6, respectively)."Clinical features: Signs include erythrodontia (brownish-discolored teeth), brownish urine and bones, with the teeth and bones fluorescent with UV light. Some affected cats have low levels of hemoglobin and iron, decreased hematocrit and mean corpuscular volume, and increased reticulocyte counts. Affected cats have half-normal activity of hydroxymethylbilane (HMB) synthase, and normal uroporphyrinogen III synthase (UROS) activity. Urinary aminolevulinic acid (ALA), porphobilinogen (PBG), uroporphyrin, and coproporphyrin levels are all elevated (Clavero et al., 2010).
Cats presenting with brown discolored teeth may have either AIP or CEP. There has so far been one genetically confirmed feline case of CEP (see OMIA 001175-9685), so cats showing these signs are more likely to have AIP.Pathology: Affected cats have decreased levels of HMB-synthase, which disrupts the normal heme synthesis pathway. This leads to an accumulation of porphyrins (URO I and COPRO I) in teeth and bones, causing discoloration. The porphyrins are also excreted in urine, causing the brownish tint (Clavero et al., 2010). Control: Testing of cats that present with AIP-like signs is recommended. Breeding of cats with this condition is discouraged. Genetic testing: Cats presenting with brown discolored teeth and brown urine should be tested for the causative mutations in the HMBS gene. These cats should also be tested for two mutations in the UROS gene that can cause CEP (see OMIA 001175-9685), a similar condition that is caused by a mutation in a different gene. Breeds: Domestic Shorthair, Siamese. Associated gene:
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|HMBS||hydroxymethylbilane synthase||Felis catus||D1||NC_018732.3 (16537348..16545198)||HMBS||Homologene, Ensembl, NCBI gene|
By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.
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.
|Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Year Published||PubMed ID(s)||Acknowledgements|
|Porphyria, acute intermittent||HMBS||deletion, small (<=20)||c.107_110delACAG||p.D36Vfs 6||2013||24239138|
|Porphyria, acute intermittent||HMBS||insertion, small (<=20)||c.189dupT||2010||19934113|
|Porphyria, acute intermittent||HMBS||deletion, small (<=20)||c.842_844delGAG||2013||24239138|
|Porphyria, acute intermittent||HMBS||missense||Felis_catus_6.2||D1||g.16391905G>A||c.250G>A||p.A84T||2013||24239138||Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool|
|Porphyria, acute intermittent||HMBS||missense||Felis_catus_6.2||D1||g.16392832||c.445C>T||p.R149W||2013||24239138||Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool|
|Porphyria, acute intermittent||HMBS||splicing||Felis_catus_6.2||D1||g.16394866G>A||c.826-1G>A||2013||24239138||Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool|
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.
|2013||Clavero, S., Ahuja, Y., Bishop, D.F., Kwait, B., Haskins, M.E., Giger, U., Desnick, R.J. :|
|Diagnosis of feline acute intermittent porphyria presenting with erythrodontia requires molecular analyses. Vet J :, 2013. Pubmed reference: 24239138. DOI: 10.1016/j.tvjl.2013.10.008.|
|2010||Clavero, S., Bishop, DF., Haskins, ME., Giger, U., Kauppinen, R., Desnick, RJ. :|
|Feline acute intermittent porphyria: a phenocopy masquerading as an erythropoietic porphyria due to dominant and recessive hydroxymethylbilane synthase mutations. Hum Mol Genet 19:584-96, 2010. Pubmed reference: 19934113. DOI: 10.1093/hmg/ddp525.|
|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.|
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