OMIA 000625-9913 : Mannosidosis, alpha in Bos taurus

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

Possibly relevant human trait(s) and/or gene(s) (MIM number): 248500

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: 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), 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)

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
MAN2B1 mannosidase alpha class 2B member 1 Bos taurus 7 NC_037334.1 (12838426..12853766) MAN2B1 Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective.

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Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Galloway Mannosidosis, alpha MAN2B1 missense UMD3.1 7 g.13956640G>A c.662G>A p.R221H 1997 9208932 Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool
Angus Murray Grey Mannosidosis, alpha MAN2B1 missense UMD3.1 7 g.13957949T>C c.961T>C p.F321L 1997 9208932 Breed and variant information kindly provided or confirmed by Matt McClure and Jennifer McClure from "Understanding Genetics and Complete Genetic Disease and Trait Definition (Expanded 2016 Edition)" (https://www.icbf.com/wp/?page_id=2170)

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2009 Khan, J.M., Ranganathan, S. :
A multi-species comparative structural bioinformatics analysis of inherited mutations in alpha-D-mannosidase reveals strong genotype-phenotype correlation. BMC Genomics :S33, 2009. Pubmed reference: 19958498. DOI: 10.1186/1471-2164-10-S3-S33.
2006 Faid, V., Evjen, G., Tollersrud, OK., Michalski, JC., Morelle, W. :
Site-specific glycosylation analysis of the bovine lysosomal alpha-mannosidase. Glycobiology 16:440-61, 2006. Pubmed reference: 16449350. DOI: 10.1093/glycob/cwj081.
2003 Heikinheimo, P., Helland, R., Leiros, HK., Leiros, I., Karlsen, S., Evjen, G., Ravelli, R., Schoehn, G., Ruigrok, R., Tollersrud, OK., McSweeney, S., Hough, E. :
The structure of bovine lysosomal alpha-mannosidase suggests a novel mechanism for low-pH activation. J Mol Biol 327:631-44, 2003. Pubmed reference: 12634058.
2002 Jolly, R.D. :
Mannosidosis in cattle and its control New Zealand Veterinary Journal 50:90, 2002. Pubmed reference: 16032247.
1999 Gelhaus, A., Hanotte, O., Horstmann, R.D., Teale, A.J. :
Linkage mapping of the bovine lysosomal alpha-mannosidase (MANB) gene Animal Genetics 30:227-228, 1999. Pubmed reference: 10442991.
Panter, K.E., Ralphs, M.H., James, L.F., Stegelmeier, B.L., Molyneux, R.J. :
Effects of locoweed (Oxytropis sericea) on reproduction in cows with a history of locoweed consumption Veterinary & Human Toxicology 41:282-286, 1999.
1998 Healy, P.J., Malmo, J. :
Roles for biochemical and polymerase chain reaction technologies in diagnosis and control of bovine alpha-mannosidosis Australian Veterinary Journal 76:699-700, 1998. Pubmed reference: 9830573.
1997 Berg, T., Healy, P.J., Tollersrud, O.K., Nilssen, O. :
Molecular heterogeneity for bovine alpha-mannosidosis - PCR based assays for detection of breed-specific mutations Research in Veterinary Science 63:279-282, 1997. Pubmed reference: 9491457.
Riise, H.M.F., Berg, T., Nilssen, O., Romeo, G. :
Genomic structure of the human lysosomal alpha-mannosidase gene (manb) Genomics 42:200-207, 1997. Pubmed reference: 9192839. DOI: 10.1006/geno.1997.4668.
Tollersrud, O.K., Berg, T., Healy, P., Evjen, G., Ramachandran, U., Nilssen, O. :
Purification of bovine lysosomal alpha-mannosidase, characterization of its gene and determination of two mutations that cause alpha-mannosidosis European Journal of Biochemistry 246:410-419, 1997. Pubmed reference: 9208932.
1996 Healy, P.J. :
Testing for undesirable traits in cattle - an Australian perspective Journal of Animal Science 74:917-922, 1996. Pubmed reference: 8728015.
1995 Healy, P.J., Dennis, J.A., Moule, J.F. :
Use of hair root as a source of DNA for the detection of heterozygotes for recessive defects in cattle Australian Veterinary Journal 72:392, 1995. Pubmed reference: 8599573.
Stegelmeier, B.L., James, L.F., Panter, K.E., Molyneux, R.J. :
Serum swainsonine concentration and alpha-mannosidase activity in cattle and sheep ingesting Oxytropis sericea and Astragalus lentiginosus (locoweeds) American Journal of Veterinary Research 56:149-154, 1995. Pubmed reference: 7717575.
1994 Healy, P.J., Dennis, J.A., Nicholls, P.J., Reichmann, K.G. :
Haemopoietic Chimaerism - A Complication in Heterozygote Detection Tests for Inherited Defects in Cattle Animal Genetics 25:1-6, 1994. Pubmed reference: 8161014.
1992 Degasperi, R., Aldaher, S., Winchester, B.G., Warren, C.D. :
Substrate Specificity of the Bovine and Feline Neutral alpha- Mannosidases Biochemical Journal 286:55-63, 1992. Pubmed reference: 1520284.
1991 Degasperi, R., Aldaher, S., Daniel, P.F., Winchester, B.G., Jeanloz, R.W., Warren, C.D. :
The Substrate Specificity of Bovine and Feline Lysosomal alpha-D-Mannosidases in Relation to alpha-Mannosidosis Journal of Biological Chemistry 266:16556-16563, 1991. Pubmed reference: 1885586.
1990 Healy, P.J., Harper, P.A.W., Dennis, J.A. :
Phenotypic Variation in Bovine Alpha-Mannosidosis Research in Veterinary Science 49:82-84, 1990. Pubmed reference: 2382061.
1981 Barlow, R.M., MacKellar, A., Newlands, G., Wiseman, A., Berrett, S. :
Mannosidosis in Aberdeen Angus cattle in Britain Veterinary Record 109:441-445, 1981. Pubmed reference: 7303458.
Healy, P.J. :
Modified granulocyte test for determination of mannosidosis genotype of cattle Research in Veterinary Science 30:281-, 1981. Pubmed reference: 7020017.
1980 Dorling, P.R., Huxtable, C.R., Colegate, S.M. :
Inhibition of lysosomal alpha-mannosidase by swainsonine, an indolizidine alkaloid isolated from Swainsona canescens. Biochem J 191:649-51, 1980. Pubmed reference: 6786280.
Jolly, R.D., Townsley, R.J. :
Genetic screening programmes: an analysis of benefits and costs using the bovine mannosidosis scheme as a model New Zealand Veterinary Journal 28:3-6, 1980. Pubmed reference: 6776451. DOI: 10.1080/00480169.1980.34676.
Mason, R.W. :
Mannosidosis of cattle: a storage disease Journal of Agriculture, Tasmania 51:94-95, 1980.
1979 Leipold, H.W., Smith, J.E., Jolly, R.D., Eldridge, F.E. :
Mannosidosis of Angus calves Journal of the American Veterinary Medical Association 175:457-459, 1979. Pubmed reference: 500478.
1978 Burditt, L.J., Phillips, N.C., Robinson, D., Winchester, B.G., Van-de-Water, N.S., Jolly, R.D. :
Characterization of the mutant alpha-mannosidase in bovine mannosidosis. Biochem J 175:1013-22, 1978. Pubmed reference: 743225.
Burditt, L.J., Winchester, B.G., Van-de-Water, N.S., Jolly, R.D. :
Preliminary characterization of the mutant alpha-mannosidase in bovine mannosidosis [proceedings]. Biochem Soc Trans 6:438-40, 1978. Pubmed reference: 648729.
Dorling, P.R., Huxtable, C.R., Vogel, P. :
Lysosomal storage in Swainsona spp. toxicosis: an induced mannosidosis. Neuropathol Appl Neurobiol 4:285-95, 1978. Pubmed reference: 703929.
Healy, P.J., Nicholls, P.J., Butrej, P. :
A granulocyte test for detection of cattle heterozygous for mannosidosis. Clin Chim Acta 88:429-35, 1978. Pubmed reference: 699335.
Jolly, R.D. :
Mannosidosis and its control in Angus and Murray Grey cattle New Zealand Veterinary Journal 26:194-198, 1978. Pubmed reference: 279874. DOI: 10.1080/00480169.1978.34539.
Jolly, R.D., Thompson, K.G. :
The pathology of bovine mannosidosis. Vet Pathol 15:141-52, 1978. Pubmed reference: 664183.
1977 Jolly, R.D., Janmaat, A., van de Water, N.S. :
Heterozygote detection: a comparative study using neutrophils, lymphocytes, and two reference parameters in the bovine mannosidosis model. Biochem Med 18:402-9, 1977. Pubmed reference: 597287.
Jolly, R.D., Thompson, K.G. :
Mannosidosis - Pathogenesis of lesions in exocrine cells Journal of Pathology 121:59-61, 1977. Pubmed reference: 874628. DOI: 10.1002/path.1711210109.
Phillips, N.C., Winchester, B.G., Jolly, R.D. :
A serological investigation into the acidic -D-mannosidase in normal Angus cattle and in a calf with mannosidosis Biochemical Journal 163:269-277, 1977. Pubmed reference: 869926.
1976 Healy, P.J., Cole, A.A. :
Heterozygotes for mannosidosis in Angus and Murray Grey cattle Australian Veterinary Journal 52:385-386, 1976. Pubmed reference: 985261.
Jolly, R.D., Thompson, K.G. :
Mannosidosis - a cause of neonatal mortality in Angus calves New Zealand Veterinary Journal 24:184-185, 1976. Pubmed reference: 1070618. DOI: 10.1080/00480169.1976.34313.
Jolly, R.D., Thompson, K.G., Murphy, C.E., Manktelow, B.W., Bruere, A.N., Winchester, B.G. :
Enzyme replacement therapy--an experiment of nature in a chimeric mannosidosis calf. Pediatr Res 10:219-24, 1976. Pubmed reference: 942612. DOI: 10.1203/00006450-197604000-00003.
Thompson, K.G., Jolly, R.D., Winchester, B.G. :
Mannosidosis--use of reference enzymes in heterozygote detection. Biochem Med 15:233-40, 1976. Pubmed reference: 999655.
Thompson, KG., Jolly, RD., Rammell, CG. :
Lymphocyte alpha-mannosidase -- a supplementary test for determining mannosidosis genotype in cattle. N Z Vet J 24:167-70, 1976. Pubmed reference: 1070614. DOI: 10.1080/00480169.1976.34309.
Winchester, BG., Van-de-Water, NS., Jolly, RD. :
The nature of the residual alpha-mannosidase in plasma in bovine mannosidosis. Biochem J 157:183-8, 1976. Pubmed reference: 9065.
1975 Jolly, R.D. :
Mannosidosis of Angus cattle: a prototype control program for some genetic diseases Advances in Veterinary Science and Comparative Medicine 19:1-21, 1975. Pubmed reference: 1978.
Jolly, R.D., Thompson, K.G., Winchester, B.G. :
Bovine mannosidosis--a model lysosomal storage disease. Birth Defects Orig Artic Ser 11:273-8, 1975. Pubmed reference: 100.
Landblad, A., Nilsson, B., Norden, N.E., Svensson, S., Ockerman, P.A., Jolly, R.D. :
A urinary pentasaccharide in bovine mannosidosis European Journal of Biochemistry 59:601-605, 1975. Pubmed reference: 1204626.
1974 Jolly, R.D. :
Mannosidosis of children, other inherited, lysosomal storage diseases. Mannosidosis (pseudolipieosis) of Angus cattle American Journal of Pathology 74:211-214, 1974. Pubmed reference: 4809314.
Jolly, R.D., Digby, J.G., Rammell, C.G. :
A mass screening programme of Angus cattle for the mannosidosis genotype. Prototype programme for control of inherited diseases in animals New Zealand Veterinary Journal 22:218-222, 1974. Pubmed reference: 4534009. DOI: 10.1080/00480169.1974.34171.
Jolly, R.D., Thompson, K.G., Tse, C.A. :
Evaluation of a screening programme for identification of mannosidosis heterozygotes in Angus cattle New Zealand Veterinary Journal 22:185-190, 1974. Pubmed reference: 4531595. DOI: 10.1080/00480169.1974.34163.
Jolly, R.D., Thompson, K.G., Tse, C.A., Munford, R.E., Merrall, M. :
Identification of mannosidosis heterozygotes - factors affecting normal plasma alpha mannosidase levels New Zealand Veterinary Journal 22:155-162, 1974. Pubmed reference: 4531604. DOI: 10.1080/00480169.1974.34156.
Phillips, N.C., Robinson, D., Winchester, B.G., Jolly, R.D. :
Mannosidosis in Angus cattle. The enzymic defect Biochemical Journal 137:363-371, 1974. Pubmed reference: 4207387.
1973 Jolly, R.D., Tse, C.A., Greenway, R.M. :
Plasma mannosidase activity as a means of detecting mannosidosis heterozygotes. N Z Vet J 21:64-9, 1973. Pubmed reference: 4517610. DOI: 10.1080/00480169.1973.34079.
Norden, N.E., Lundblad, A., Ockerman, P.A., Jolly, R.D. :
Mannosidosis in Angus cattle : partial characterization of two mannose containing oligosaccharides Federation of European Biochemical Societies Letters 35:209-212, 1973. Pubmed reference: 4744388.
1972 Hocking, J.D., Jolly, R.D., Batt, R.D. :
Deficiency of alpha mannosidase in Angus cattle : An inherited lysosomal storage disease Biochemical Journal 128:69-79, 1972. Pubmed reference: 4673577.
1970 Jolly, R.D. :
Diagnosis and control of pseudolipidosis of Angus calves New Zealand Veterinary Journal 18:228-229, 1970. Pubmed reference: 5285875. DOI: 10.1080/00480169.1970.33909.

Edit History


  • Created by Frank Nicholas on 15 Nov 2005
  • Changed by Frank Nicholas on 09 Dec 2011
  • Changed by Frank Nicholas on 03 Sep 2012
  • Changed by Frank Nicholas on 11 Dec 2013