OMIA 001493-9685 : Porphyria, acute intermittent in Felis catus

Possibly relevant human trait(s) and/or gene(s) (MIM number): 176000

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Dominant

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2010

Species-specific symbol: Feline AIP

Species-specific description: Acute intermittent porphyria (AIP) is a disorder of heme synthesis characterized by erythrodontia (brown discolored teeth) that fluoresce pink under UV light and reddish-brown urine. The presenting signs are very similar to those of congenital erythropoietic porphyria (CEP, OMIA 001175-9685). Cats with AIP have half normal hydroxymethylbilane (HMB) synthase activity, a necessary enzyme in the heme synthesis pathway. Testing of cats that present with AIP-like signs is recommended, since these cats may have either AIP or CEP. Breeding of cats with either condition is discouraged.

Edited by Dr. Mark Haskins

Inheritance: 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

Variants

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

References


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.

Edit History


  • Created by Frank Nicholas on 28 Jun 2010
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  • Changed by Frank Nicholas on 09 Dec 2011
  • Changed by Frank Nicholas on 07 Dec 2012
  • Changed by Frank Nicholas on 22 Nov 2013