Possibly relevant human trait(s) and/or gene(s) (MIM number): 215700

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 1989

Cross-species summary: The clinical signs of this disorder result from ammonia poisoning, due to a fault in the urea cycle. This cycle is the biochemical process by which potentially toxic ammonia (a by-product of catabolism of proteins) is converted to urea, which is excreted in urine. The fault in the cycle arises from a deficiency of one of the enzymes involved in the cycle, namely argininosuccinate synthetase (ASS). The absence of this enzyme leads to a buildup of citrulline and, more seriously, of ammonia.

Species-specific description: To date, all cases of this lethal disorder in cattle appear to be due to the same mutation, namely a nonsense mutation in the 5th of 9 exons of the ASS gene. Normal bovine ASS is a peptide containing 412 amino acids; the mutation occurs in the 86th codon.

Mapping: 11q28

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Dennis et al. (1989) reported the causative mutation as a C>T transition, altering arginine-86 (CGA) to a nonsense codon (TGA) (Mohammad Shariflou 10/11/2006; FN 19 Sept 2012).

Clinical features: Normal at birth, but signs of depression within a few hours; tongue protrusion; unsteady gait; aimless wandering; frothing at mouth; head pressing; death within 3-5 days

Genetic testing: The .0001 mutation destroys a recognition sequence for the restriction enzyme AvaI, thereby generating an RFLP. Dennis et al. (1989) developed a PCR genotyping test based on this RFLP, with primers 100 bp on either side of the mutation site. After AvaI digestion of the PCR product, homozygous normals show a single 100-bp band (containing the fragments on either side of the mutation site), heterozygotes show a 100-bp band and a 200-bp band, and affected calves show a 200-bp band only. This test is now regularly performed on hair follicles, which are far easier to collect from the field than blood (Healy, pers. comm.).

Associated gene: