OMIA 000194-9913 : Citrullinaemia in Bos taurus

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:

Symbol Description Species Chr Location OMIA gene details page Other Links
ASS1 argininosuccinate synthase 1 Bos taurus 11 NC_037338.1 (100770227..100822223) ASS1 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
Holstein-Friesian Citrullinaemia ASS1 nonsense (stop-gain) UMD 3.1 11 g.100802781C>T c.256C>T p.R86* 1989 2813370 Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool; Breed 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.
2018 Zepeda-Batista, J.L., Parra-Bracamonte, G.M., Núñez-Domínguez, R., Ramírez-Valverde, R., Ruíz-Flores, A. :
Screening genetic diseases prevalence in Braunvieh cattle. Trop Anim Health Prod :, 2018. Pubmed reference: 30014197. DOI: 10.1007/s11250-018-1655-y.
2011 Sun, D.X., Fan, X.H., Xie, Y., Chu, Q., Sun, Y., Zhang, Y., Zhang, S.L., Gong, W.J., Chen, S.H., Li, Y.H., Shi, W.H., Zhang, Y. :
Short communication: Distribution of recessive genetic defect carriers in Chinese Holstein. J Dairy Sci 94:5695-8, 2011. Pubmed reference: 22032394. DOI: 10.3168/jds.2011-4345.
2010 Meydan, H., Yildiz, MA., Agerholm, JS. :
Screening for bovine leukocyte adhesion deficiency, deficiency of uridine monophosphate synthase, complex vertebral malformation, bovine citrullinaemia, and factor XI deficiency in Holstein cows reared in Turkey. Acta Vet Scand 52:56, 2010. Pubmed reference: 20929557. DOI: 10.1186/1751-0147-52-56.
2009 Windsor, P., Agerholm, J. :
Inherited diseases of Australian Holstein-Friesian cattle. Aust Vet J 87:193-9, 2009. Pubmed reference: 19382928. DOI: 10.1111/j.1751-0813.2009.00422.x.
2006 Patel, RK., Singh, KM., Soni, KJ., Chauhan, JB., Sambasiva Rao, KR. :
Lack of carriers of citrullinaemia and DUMPS in Indian Holstein cattle. J Appl Genet 47:239-42, 2006. Pubmed reference: 16877802.
2004 Goodwin, BL., Solomonson, LP., Eichler, DC. :
Argininosuccinate synthase expression is required to maintain nitric oxide production and cell viability in aortic endothelial cells. J Biol Chem 279:18353-60, 2004. Pubmed reference: 14970240. DOI: 10.1074/jbc.M308160200.
1999 Lee, B., Dennis, J.A., Healy, P.J., Mull, B., Pastore, L., Yu, H., Aguilar-Cordova, E., O'Brien, W., Reeds, P., Beaudet, A.L. :
Hepatocyte gene therapy in a large animal: A neonatal bovine model of citrullinemia Proceedings of the National Academy of Sciences of the United States of America 96:3981-3986, 1999. Pubmed reference: 10097149.
Padeeri, M., Vijaykumar, K., Grupe, S., Narayan, M.P., Schwerin, M., Kumar, M.H. :
Incidence of hereditary Citrullinemia and bovine leucocyte adhesion deficiency syndrome in Indian dairy cattle (Bos taurus, Bos indicus) and buffalo (Bubalus bubalis) population Archiv fur Tierzucht-Archives of Animal Breeding 42:347-352, 1999.
1998 Patejunas, G., Lee, B., Dennis, J.A., Healy, P.J., Reeds, P.J., Yu, H., Frazer, M., Mull, B., Warman, A.W., Beaudet, A.L., Obrien, W.E. :
Evaluation of gene therapy for citrullinaemia using murine and bovine models Journal of Inherited Metabolic Disease 21:138-150, 1998. Pubmed reference: 9686351.
1996 Grupe, S., Dietl, G., Schwerin, M. :
Population survey of citrullinemia on german holsteins Livestock Production Science 45:35-38, 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.
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.
1993 Healy, P.J., Dennis, J.A. :
Inherited Enzyme Deficiencies in Livestock Veterinary Clinics of North America - Food Animal Practice 9:55-63, 1993. Pubmed reference: 8457930.
Healy, P., Dennis, J., Rawlinson, R., Andersson, L. :
Prenatal Diagnosis of Bovine Citrullinaemia Research in Veterinary Science 55:271-274, 1993. Pubmed reference: 8284487.
Robinson, J.L., Burns, J.L., Magura, C.E., Shanks, R.D. :
Low Incidence of Citrullinemia Carriers Among Dairy Cattle of the United-States Journal of Dairy Science 76:853-858, 1993. Pubmed reference: 8463494. DOI: 10.3168/jds.S0022-0302(93)77411-1.
1992 Dodd, P.R., Williams, S.H., Gundlach, A.L., Harper, P.A.W., Healy, P.J., Dennis, J.A., Johnston, G.A.R. :
Glutamate and gamma-Aminobutyric Acid Neurotransmitter Systems in the Acute Phase of Maple Syrup Urine Disease and Citrullinemia Encephalopathies in Newborn Calves Journal of Neurochemistry 59:582-590, 1992. Pubmed reference: 1352800.
1991 Healy, P.J., Dennis, J.A., Camilleri, L.M., Robinson, J.L., Stell, A.L., Shanks, R.D. :
Bovine Citrullinaemia Traced to the Sire of Linmack Kriss King Australian Veterinary Journal 68:155, 1991. Pubmed reference: 2069549.
Thomsen, P.D., Nielsen, J.S. :
PCR Screening for Carriers of Hereditary Citrullinaemia in Danish Holstein-Friesian Bulls Acta Veterinaria Scandinavica 32:279-282, 1991. Pubmed reference: 1803940.
Thornton, R.N., Gilmour, M.L., Rammel, C.A. :
Citrullinaemia in Friesian Calves New Zealand Veterinary Journal 39:145-146, 1991.
1990 Anon. :
Hereditary Orotic Aciduria and Citrullinemia - Bovine Models Nutrition Reviews 48:193-195, 1990.
Healy, P.J., Harper, P.A.W., Dennis, J.A. :
Bovine Citrullinaemia - A Clinical, Pathological, Biochemical and Genetic Study Australian Veterinary Journal 67:255-258, 1990. Pubmed reference: 2393373.
1989 Dennis, J.A., Healy, P.J., Beaudet, A.L., Obrien, W.E. :
Molecular Definition of Bovine Argininosuccinate Synthetase Deficiency Proceedings of the National Academy of Sciences of the United States of America 86:7947-7951, 1989. Pubmed reference: 2813370.
Harper, P.A.W., Healy, P.J., Dennis, J.A. :
Animal Model of Human Disease - Citrullinemia (Argininosuccinate Synthetase Deficiency) American Journal of Pathology 135:1213-1215, 1989. Pubmed reference: 2596577.
1988 Harper, PA., Healy, PJ., Dennis, JA., Martin, AB. :
Ultrastructural findings in citrullinaemia in Holstein-Friesian calves. Acta Neuropathol 76:306-10, 1988. Pubmed reference: 3213435.
1986 Harper, P.A.W., Healy, P.J., Dennis, J.A., O'Brien, J.J., Rayward, D.H. :
Citrullinaemia as a cause of neurological disease in neonatal Friesian calves Australian Veterinary Journal 63:373-379, 1986. Pubmed reference: 3827775.

Edit History


  • Created by Frank Nicholas on 27 Oct 2010
  • Changed by Frank Nicholas on 30 Sep 2011
  • Changed by Frank Nicholas on 09 Dec 2011
  • Changed by Frank Nicholas on 19 Sep 2012