Abstract

Abstract 3014

Poster Board II-990

Porphyrias are disorders of heme biosynthesis and are clinically classified as either erythroid with cutaneous involvement or hepatic with acute neurovisceral attacks in human patients. The clinical features, specific enzyme defects, biochemical abnormalities, and gene mutations have been extensively studied in humans. Here we describe clinical, biochemical, and molecular genetic studies of four unrelated lines of cats that appeared clinically to have a congenital erythropoietic porphyria (CEP), but were ultimately identified to have acute intermittent porphyria (AIP). The porphyric cats had erythrodontia, porphyrinuria, and mild anemia, but no evidence of acute life-threatening neurovisceral attacks or cutaneous lesions. Their urinary uroporphyrin I and coproporphyrin I concentrations were markedly increased (up to 650-fold and ∼10-fold, respectively). Their erythrocyte and hepatic uroporphyrinogen III synthase activities (deficient in CEP) were normal. However, all porphyric cats had '50% of normal hydroxymethylbilane synthase (HMBS) activity in erythrocytes and tissues, and increased levels of urinary 5-aminolevulinic acid and porphobilinogen. Moreover, porphyrin analysis of the discolored teeth from the porphyric cats revealed markedly elevated uroporphyrin I and coproporphyrin I isomers, thereby explaining their CEP-like phenotype. Sequencing the feline HMBS gene revealed different mutations in each of the four lines of porphyric cats: a T duplication in exon 5, c.189dupT (p.Leu64SerfsX65), which predicts a frameshift and premature stop codon, an in-frame 3 bp deletion in exon 14, c.842_844delGAG (p.delGly281), which is identical to a mutation causing AIP in a human patient, and two missense mutations: in exon 6,c.250G>A (p.Ala84Thr) and in exon 9, c.445C>T (p.Arg149Trp), the latter was also reported in a human AIP patient. Prokaryotic expression of the feline p.delGly281 and p.Arg149Trp mutations resulted in <1% residual activity, while the p.Ala84Thr missense mutation had ∼34% of the expressed feline HMB-synthase wild-type activity. Family studies further confirmed that the p.Ala84Thr missense mutation was inherited as an autosomal recessive trait with the porphyric cats being homozygous for the mutation and the parents and littermates being asymptomatic heterozygotes. In contrast, the porphyric cats from the other three lines were heterozygous for their mutations, thus reflecting the autosomal dominant inheritance observed in humans with AIP. While genetically-engineered mice with AIP have been generated, we describe here the first naturally-occurring animal models of dominant and recessive forms of AIP. Although the cats' phenotype is more similar to that of human patients with CEP, these cats may permit further characterization of the disease pathogenesis as well as the evaluation of therapeutic strategies for human patients with AIP including pharmacologic chaperone, gene replacement, transplantation, and stem cell therapies.

Disclosures:

No relevant conflicts of interest to declare.

Author notes

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Asterisk with author names denotes non-ASH members.