In other species: dog , killer whale , bottlenosed dolphin

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 234000 (trait) , 610619 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2015

Species-specific description: FXII-deficiency in cats is characterised by reduced FXII activity and increased APTT [activated partial thromboplastin time] values, but the condition does not appear to be associated with increased risk of bleeding (Maruyama et al., 2019).

Inheritance: Kier et al. (1980) provided evidence of autosomal recessive inheritance and reported the establishment of a colony at the University of North Carolina at Chapel Hill, derived from a gift of breeding animals from a colony established at Kansas University by Dr Bresnahan (Bender et al., 2015).

Molecular basis: Bender et al. (2015) characterised the obvious functional and comparative candidate gene for this disorder, namely the gene for factor XII, in cats: "Fourteen exons ranging in size from 57 to 222 base pairs were confirmed spanning 8 Kb on chromosome A1. The 1828–base pair feline FXII messenger RNA (mRNA) sequence contains an open reading frame that encodes a protein of 609 amino acids with high homology to human FXII protein." Subsequent sequencing in normal and affected cats identified a "single base deletion in exon 11 of the FXII coding gene in our colony of cats results in deficient FXII activity. Translation of the mRNA transcript shows a frame shift at L441 (C441fsX119) resulting in a nonsense mutation and a premature stop codon with a predicted 560–amino acid protein. The mutant FXII protein is truncated in the 3′ proteolytic light chain region of the C-terminus, explaining its loss of enzymatic activity."

By sequencing the most likely candidate gene in 6 Japanese domestic short-hair cats (2 cats with severely reduced FXII activity (7.1 % and 9.3 %, respectively) and 4 cats with moderately reduced FXII activity (range 36.0 to 46.3 %)), Maruyama et al. (2017) identified a new likely causal variant in exon 13 of the F12 gene: "Cats with severely reduced FXII activity were homozygous" for a missense mutation c.1631G>C, p.G544A; "Cats with moderately reduced FXII activity were heterozygous for this mutation". These authors also reported that "Expression studies revealed reduced secretion of p.G544A mutant FXII protein from transfected HEK293 cells compared with wild type FXII."

Maruyama et al. (2019) “ identified a novel F12 sequence variant (c.1549C>T) predicted to alter FXII expression. This nonsense mutation, located in exon 13, generated a premature stop codon in the FXII protein's catalytic domain (p.Q517Ter). .. . [The authors] did not perform in vitro FXII expression studies of the novel exon 13 nonsense mutation (c.1549C>T; p.Q517Ter), the cat whose genotype included this mutation, in addition to single copies of the common mutations, had a severe FXII-deficient phenotype.”

Clinical features: Maruyama et al. (2019) characterized the phenotypic features of FXII deficient client owned-cats: “The study set of 26 cats included 14 females … and 12 males … , with an age range of 0.5 to 16 years … . … FXII activities … ranged from 0.5 to 14% … . … The APTT [activated partial thromboplastin time] values for all cats were prolonged beyond the laboratory's cutoff value for healthy cats of 19.0 s. … Client history questionnaires were completed for 25 of the 26 cats. No cats had experienced spontaneous, non-traumatic hemorrhage, or abnormal bleeding when deciduous teeth were shed. Twenty cats … had undergone ovariohysterectomy or castration procedures and none experienced hemorrhagic complications. … The lack of abnormal bleeding, even among severely FXII deficient cats, combined with the high prevalence of the trait, supports the non-pathologic nature of inactivating F12 mutations in this species.”

Prevalence: Maruyama et al. (2019) investigated the demographics of FXII deficiency in client owned-cats: “Domestic cats were the most common breed listed across all submissions, however 14% of all FXII-deficient cats were described as non-domestic cats. In addition to “mixed breed” cats (n = 9), the pure breeds listed included Siamese (n = 17), Persian (n = 9), Maine coon (n = 5), Ragdoll (n = 5) Himalayan (n = 4), Bengal (n = 2), Siberian (n = 2), Turkish Van (n = 2), Russian blue (n = 2), and 1 each of the following breeds: Manx, Munchkin, Norwegian forest, and Oriental shorthair.”

Breeds: Bengal, Domestic Shorthair, Himalayan, Maine Coon, Manx, Munchkin, Norwegian Forest, Oriental shorthair, Persian, Ragdoll, Russian Blue, Siamese, Siberian, Turkish Van.

Associated gene: