Categories: Homeostasis / metabolism phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 176000 (trait) , 609806 (gene)

Links to MONDO diseases:

• MONDO:0008294: acute intermittent porphyria

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)."

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

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 (Cat) (VBO_0100221).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated gene: