In other species: dog , domestic cat , goat , sheep , domestic guinea pig

Categories: Lysosomal storage disease

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 248500 (trait) , 609458 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0009561: alpha-mannosidosis

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 1997

Cross-species summary: A lysosomal storage disease in which there is a buildup (storage) of mannose-rich compounds, due to the lack of the enzyme alpha-mannosidase, whose task is to cleave mannose from such compounds. Clinical signs include ataxia, head tremor, aggression, and finally paralysis and death.

Species-specific description: This was one of the first inherited lysosomal storage disorders to be studied extensively in animals. The pioneering work was done by Jolly and colleagues at Massy University in New Zealand, who developed an enzyme assay that enabled carriers to be distinguished from homozygote normals with a high degree of accuracy (Jolly et al., 1973). More than twenty years later, following the cloning and characterisation of the human gene for alpha mannosidase by Nilssen et al. (1997; Human Molecular Genetics 6:717-726), the bovine gene was cloned and characterised by Tollersud et al. (1997) who identified a different causative base substitution (giving rise to an amino-acid substitution) in each of the Angus and Galloway breeds. Berg et al. (1997) extended these results to several other derivative breeds. In summary, a G662A transition is the mutation responsible in Galloways; and a T961C transition is the causative mutation in Angus, Murray Grey and Brangus from Australia, and in Red Angus cattle imported into Australia from Canada as embryos. Given that both Galloways and Angus originated in Scotland, and that the other breeds studied are Angus derivatives, it seems that the two mutations arose in Scotland, and have then been disseminated to other parts of the world.

Inheritance: The inherited form of this disorder is a classic autosomal recessive inborn error of metabolism. Interestingly, there is a non-inherited (phenocopy) form of this disorder that occurs in any species of animal that ingests plants of the Swainsona legume genus (e.g. Darling pea). The reason for this is that plants in the Swainsona genus produce a trihydroxylated indolizidine alkaloid called swainsonine, which inhibits α-mannosidase by binding to it, thereby producing a build-up of exactly the same mannose-rich oligosaccharides that are characteristic of the inherited form of the disorder. A similar compound is produced by plants in the Astragalus and Oxytropis genera. Indeed, plants within these genera are called locoweed, because of the clinical signs they induce. Not surprisingly, these clinical signs can be induced in any animal species that grazes on the plants. For further information, see the following references in the list below: Dorling et al. (1978), Colegate et al. (1979), Dorling et al. (1980), Stegelmeier et al. (1995), Panter et al. (1999) (Adapted from Nicholas (2010) Introduction to Veterinary Genetics, Blackwell-Wiley, pp. 91-92).

Molecular basis: As reported by Tollersrud et al. (1997), the bovine gene spans 16 kb and comprises 24 exons. The open reading frame comprises 2997 bases encoding a signal peptide of 50 amino acids plus a further 949 amino acids, which are cleaved into five peptides in the mature enzyme. In Angus cattle, a T961>C transition results in a Phe321>Leu substitution. In Galloway cattle, a G662>A transition results in a Arg221>His substitution.

Prevalence: Prior to the introduction of the control program in 1974 in New Zealand, approximately 3000 Angus calves were affected each year in that country.

Control: The control of alpha mannosidosis in Angus and Murray Grey cattle by means of an enzyme assay for detection of carriers is the classic textbook case of this type of control program (Jolly et al., 1974; Jolly, 1975; Jolly, 1978). Following the New Zealand success, Healy and colleagues conducted an equally successful control program in Australian Angus (Healy, 1996). It is interesting to note that these successful control programs were conducted in the pre-molecular age.

Genetic testing: PCR genotyping tests are described by Berg et al. (1997)

Breeds: Angus (Cattle) (VBO_0000104), Galloway (Cattle) (VBO_0000207), Murray Grey (Cattle) (VBO_0000312).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: