In other species: water buffalo

Categories: Mortality / aging (incl. embryonic lethal)

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 258900 (trait) , 613891 (gene)

Links to MONDO diseases:

• MONDO:0009797: orotic aciduria

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 1993

Cross-species summary: Uridine monophosphate synthase (UMPS) is the enzyme responsible for converting orotic acid to uridine monophosphate (UMP), which is an essential component of pyrimidine nucleotides. This enzyme actually has two enzymatic functions: orotic phosphoribosyltransferase (OPRTase) and orotidine monophosphate decarboxylase (OMPDCase), corresponding to the last two steps in pyrimidine synthesis. Since pyrimidines are vital ingredients of nucleic acids, it follows that a deficiency of UMPS can have quite severe consequences.

Species-specific name: Haplotype HHD

Species-specific symbol: DUMPS; HHD

Species-specific description: This disorder is of particular interest in cattle, because it is one of the few cases in which an embryonic lethal has been identified. (By their very nature, embryonic lethals are difficult to identify; their only manifestation is a return to service.) To date, the only known cause of this disorder in cattle is a nonsense mutation in codon 405 of the UMPS gene, resulting in a complete deficiency of functional UMPS (Schwenger et al., 1993). Since nucleotides are required in such vast quantities during embryonic development, it is not surprising that homozygosity for the nonsense mutation results in embryonic death around 40 days in utero. The practical effect of this disorder is that carrier cows show a higher rate of return to service, because some of their pregnancies end in early natural abortion. Given that returns to service can have so many different causes, it would not have been possible to identify the mutation from reproductive records. How, then, was this embryonic lethal mutation detected initially? The answer is: by chance! As part of a nutrition study at the University of Illinois, the level of orotic acid was determined in the milk of cows in the university herd. Some cows had exceptionally high levels of this acid, and one possible explanation was that they were deficient in UMPS. Subsequent biochemical tests showed that these cows had only 50% of the normal activity of this enzyme (reviewed by Shanks and Robinson, 1990). Inheritance and molecular studies finally brought the whole story to light.

Inheritance: DUMPS is an autosomal recessive embryonic lethal.

Mapping: The UMPS gene has been mapped to the middle of chromosome 1 (q31-36) (Barendse et al., 1993; Friedl and Rottmann, 1994; Ryan et al., 1994). [Compiled by Imke Tammen]

In the course of their large-scale study of BovineSNP50 BeadChip haplotypes that are common but never homozygous, VanRaden et al. (2011) confirmed the mapping of this disorder to BTA1 at 55-73Mb (UMD 3.0 genome assembly).

Molecular basis: By cloning and sequencing a very likely candidate gene (based on knowledge that the bovine disorder is due to deficiency of uridine monophosphate sythetase), Schwenger et al. (1993) identified a C>T transition in the bovine UMPS gene as a causal mutation.

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Clinical features: Carriers are phenotypically normal, but have only half the normal activity of uridine monophosphate synthase (Harden and Robinson, 1987). Also, during lactation, carriers excrete an elevated level of orotic acid in milk and urine (Robinson et al., 1984). Carrier x carrier matings require approximately 3.1 services per calving, compared to 2.0 for normal x normal matings. [Compiled by Imke Tammen]

Genetic testing: Knowledge that the causal mutation removes a recognition sequence for the restriction enzyme AvaI immediately gave rise to a DNA test.

Breed: Holstein Friesian (Cattle) (VBO_0000239).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated gene: