Muscle weakness, MW (CACNA1S-related)

Gene: CACNA1S

Transmission: Autosomal recessive (incomplete penetration)

For an autosomal recessive genetic disease an animal must have two copies of the mutation in question to be at risk of developing the disease.  Both parents of an affected animal must be carriers of at least one copy of the mutation.  Animals that have only one copy of the mutation are not at risk of developing the disease but are carrier animals that can pass the mutation on to future generations.

Mutation: Substitution, CACNA1S gene: c.3853G>A, p.(Gly11285Ser), Chr.16.

Medical system: Muscular

Breed: Holstein

Age of onset of symptoms: Neonatal period.

Calves can have difficulty in standing after birth for a variety of reasons, including environmental causes such as physical injury or possible genetic causes.  A group of 24 Holstein calves in the United States showing variable signs of unexplained muscle weakness and inability to stand (astasia) was studied.  A molecular analysis of these calves identified a homozygous mutation in the CACNA1S gene.   The CACNA1S gene codes for a voltage dependant calcium channel protein found in skeletal muscles.  In humans, mutations in the CACNA1S gene can be a contributing cause of several genetic diseases involving muscles.  In the Holstein calf study, pedigree analysis identified a common ancestor in a bull born in 2008 who had a prolific son born in 2010.  In a study of Holstein bulls in Poland, a carrier frequency for the CACNA1S mutation of 38% was determined.  In studies in Japan and in Australia, carrier animals as well as affected double mutant animals were identified.

The use of high-performance sires has contributed to increased production in the modern dairy industry, and the dissemination of the desirable genetics of these animals is facilitated by reproductive technologies such as artificial insemination, in vitro fertilisation and embryo transfer.  This has inadvertently contributed to reduced genetic variability and increased incidence of recessive genetic diseases within herds.  Muscle weakness disease in the Holstein calves can be considered a genetic disease whose frequency was amplified due to the use of popular sires that were carriers for the CACNA1S mutation and the international distribution of their semen.  A DNA test is now available that will allow breeders and breed companies to identify carrier animals for the CACNA1S gene mutation to eliminate this genetic defect from their animals.

References:

OMIA link: [2819-9913]

Ciacia MG, Phipps AJ. (2025) Early-onset muscle weakness syndrome (MW) in an Australian Holstein calf. Aust Vet J 103:298-303. [pm/40033903]

Al-Khudhair A, VanRaden PM, Null DJ, et al. (2024) New mutation within a common haplotype is associated with calf muscle weakness in Holsteins. J Dairy Sci 107:3768-3779. [pm/38246583]

Inokuma H, Maezawa M, Miyazaki Y, et al. (2024) A clinical case of CACNA1S-related muscle weakness in a Holstein calf with congenital astasia diagnosed by a genotyping test of stored blood. J Vet Med Sci 87:28-31. [pm/39551494]

Kamiński S. (2024) Muscle Weakness – new genetic defect transmitted to Polish Holstein-Friesian cattle. Pol J Vet Sci 27:651-653. [pm39736039]

With contributions by: Eve-Marie Lemire and Anne-Gabrielle Piché, Class of 2030, Faculty of Veterinary Medicine, University of Montreal.  (Translation: DWS).