OMIA:000194-9913 : Citrullinaemia in Bos taurus (taurine cattle)

In other species: indicine cattle (zebu)

Categories: Homeostasis / metabolism phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 215700 (trait) , 603470 (gene)

Links to relevant human diseases in MONDO:

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.).

Breeds: Blanco Orejinegro, Colombia (Cattle) (VBO_0004602), Brown Swiss (Cattle) (VBO_0000166), Holstein Friesian (Cattle) (VBO_0000239).
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:

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


By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.

OMIA Variant ID Breed(s) Variant Phenotype Gene Allele Type of Variant Source of Genetic Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
289 Blanco Orejinegro, Colombia (Cattle) Brown Swiss (Cattle) Holstein Friesian (Cattle) Citrullinaemia ASS1 nonsense (stop-gain) Naturally occurring variant ARS-UCD1.2 11 g.100781668C>T c.256C>T p.(R86*) Variant initially identified in Holstein Friesian and later reported in additional breeds: PMID:30014197, PMID:34779908. 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)" (

Cite this entry

Nicholas, F. W., Tammen, I., & Sydney Informatics Hub. (2023). OMIA:000194-9913: Online Mendelian Inheritance in Animals (OMIA) [dataset].


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.

2023 Sudhakar, A., Nayee, N., Saha, S., Donthula, S.K., Poojara, H.V., Gohil, T., Patel, A.C., Maurya, B.K. :
Role of genetic introgression in introducing mutant alleles in Bos indicus cattle and prevalence of lethal genetic disorders in Bos taurus × Bos indicus and Bos indicus cattle in India. Trop Anim Health Prod 55:399, 2023. Pubmed reference: 37940810. DOI: 10.1007/s11250-023-03798-8.
2021 Caivio-Nasner, S., López-Herrera, A., González-Herrera, L.G., Rincón, J.C. :
Frequency of genotypic markers for genetic disorders, colour, polledness, and major genes in Blanco Orejinegro cattle. Trop Anim Health Prod 53:546, 2021. Pubmed reference: 34779908. DOI: 10.1007/s11250-021-02990-y.
2019 Zepeda-Batista, J.L., Parra-Bracamonte, G.M., Núñez-Domínguez, R., Ramírez-Valverde, R., Ruíz-Flores, A., 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 51:25-31, 2019. 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., Dennis, J., Rawlinson, R., Andersson, L. :
Prenatal Diagnosis of Bovine Citrullinaemia Research in Veterinary Science 55:271-274, 1993. Pubmed reference: 8284487.
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.
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: 3827779.

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
  • Changed by Imke Tammen2 on 04 Jul 2023
  • Changed by Imke Tammen2 on 08 Oct 2023