Genetic Marker Identified for Bovine Familial Convulsions and Ataxia in Angus Cattle
by Jenny Alonge
Texas A&M College of Agriculture and Life Sciences Department of Animal Science researchers published an article in the March 2024 issue of Animal Genetics describing how they identified a de novo mutation in CACNA1A associated with autosomal dominant bovine familial convulsions and ataxia in Angus cattle.
Bovine familial convulsions and ataxia
Also known as cerebellar abiotrophy, bovine familial convulsions and ataxia (BFCA) was first described in Angus cattle in 1968. Affected calves typically exhibit seizures and ataxia during the first few days of life, and calves that seemingly recover may relapse weeks later, while others survive and outgrow the seizures by 2 years of age. BFCA causes no gross lesions, but microscopic lesions include Purkinje cell degeneration and swelling in the cerebellar cortex’s lingual and uvula. Clinical disease seems to precede histologic lesion development. Cases identified between 1968 and 2004 were thought to be caused by unique autosomal dominant variants with incomplete penetrance.
In December 2016, an East Texas cattle operation rancher observed ataxia and seizures in nine calves (Group A). He also noted that six calves were stillborn or died shortly after birth and 13 females did not deliver calves. Routine screening for conditions that cause neurologic signs, stillbirths, and pregnancy loss did not provide a definitive diagnosis, but signs were consistent with BFCA. The affected calves were all sired by one bull. When 36 more cows were bred to the bull, 12 calves were affected, supporting the hypothesized dominant inheritance mode.
Whole genome sequencing
Twenty-five cows at Texas A&M University and 11 cows at the University of Illinois were artificially inseminated with samples from the BFCA bull to control for environment and to provide material for sequence analysis. The Texas A&M cows produced two stillbirths, 11 neurologic calves, and 12 normal calves (Group B), and the University of Illinois cows produced one neurologic calf (Group C). DNA was isolated from the calves’ ear tissue and blood, the sire’s semen, and blood cards using the Gentra Puregene Blood Kit.
Whole genome sequencing (WGS) was performed to explore genotypic variation associated with BFCA in this lineage, with the goal of finding the origin of the disease in this cattle family.
Candidate variants
In the six affected calves, seven unaffected calves, the sire, and 135 control cattle, 66.5 million variants were identified. After filtering, 252 loci met the criteria for a hypothesized dominant condition, and variant effect predictor (VEP) predicted that five variants would have either a moderate or high impact on gene function. The variants affected gene IDs ECT2, CACNA1A, ATP10B, ABCC4, and RBM20. The ECT2, ABCC4, and RBM20 variants were deemed unlikely causes, because they were identified in cattle without BFCA clinical signs and their presence was inconsistent in affected calves. The ATP10B variant was present in two unaffected calves and was not considered a primary candidate. The remaining variant in CACNA1A was prioritized as a candidate for causing BFCA in this lineage, because of its expected impact on gene function and its presence in all but one of the affected calves and absence in the controls.
Candidate variant genotyping
Using Sanger sequencing, the researchers found that all ataxic calves in Groups A and C were heterozygous for the CACNA1A variant, while the variant was not present in the unaffected calves. The variant was not present in additional relatives, including the sire and dam of the bull that sired the affected calves. The CACNA1A variant was not identified in WGS data from the University of Missouri, which included 5,500 cattle, or from WGS data from the USDA Meat Animal Research Center database.
Conclusion
Based on sequence analysis of the sire and his calves born to three different herds and genotype data of additional related and unrelated animals, the researchers strongly suspect that the chr7g.123670=906C>T variant of CACNA1A is responsible for de novo in the sire and for the BFCA signs observed in his offspring.
The CACNA1A protein is involved in calcium-dependent processes such as neurotransmitter release and muscle contractions, and several variants in the protein are associated with dominant episodic ataxia in humans.
Finding the genetic marker allows producers to select against this BFCA strain, helping to eliminate this genetic form of ataxia from the population.
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