In other species: dog

Categories: Homeostasis / metabolism phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 266200 (trait) , 609712 (gene)

Links to MONDO diseases:

• MONDO:0009950: pyruvate kinase deficiency of red cells

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 1997

Cross-species summary: Also known as PK deficiency

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Giger et al. (1997) identified a causative mutation as a splicing defect in the R/L-PK gene that gives rise to 13-bp deletion (Barrs et al., 2009). The gene symbol is now PKLR. Grahn et al. (2012) reported that the splicing defect and hence deletion is a consequence of a "a guanine to adenine transition in intron 5, 304 bp 3' of the exon 5 splice-donor site and 53 bp upstream from the exon 6 splice-acceptor site ["c.693+304G>A"]. The mechanism by which this mutation results in the erroneous splicing of exons 5 and 6 has yet to be determined."

Clinical features: Pyruvate kinase (PK) is an essential catalyst in the production of ATP, PK deficiency (PKD) results in ATP depletion. This leads to shortened erythrocyte life span and haemolytic anaemia (Barrs et al., 2009; Al-Samkari et al., 2020). Although carriers are asymptomatic, only half of the normal PK activity is expressed (Kohn & Fumi 2008). Due to chronic, intermittent haemolytic anaemia, common PKD clinical signs include lethargy, weight loss, pale mucous membrane, inappetence, and jaundice. Blood work usually indicates anaemia with mild to moderate reticulocytosis and hyperbilirubinaemia. The severity of clinical signs and the age on onset is highly variable, ranging from one month to five years (Kohn & Fumi, 2008; Barrs et al., 2009; Grahn et al., 2012).

IT thanks DVM student Alice Lao, who provided the basis of this contribution in May 2023.

Prevalence: Grahn et al. (2012) genotyped "14,179 cats representing 40 breeds or populations" for the causal (intronic) transition. The mutation was present in 13 breeds and two other populations (random-bred cats and unspecified cats). Within these 15 breeds/populations that have the mutation, its frequency ranges "from 0.078% in the Exotic Shorthair to 12.97% in the Bengal", with an average frequency of 9.35%.

Breeds: Abyssinian (Cat) (VBO_0100000), Somali (Cat) (VBO_0100229).

Associated gene: