Identification of the causative mutation of congenital pseudo-myotonia in Chianina cattle

Abstract: Congenital pseudo-myotonia (PMT) in Chianina cattle is a muscle function disorder which is mainly characterized by an exercise-induced muscle contracture which prevents animals from performing muscular activities more intense than a simple walk at a slow pace. Mutations in the human ATP2A1 gene, encoding a fast-twitch skeletal-muscle Ca2+ ATPase (SERCA1), cause Brody myopathy, a very similar rare autosomal recessive disorder characterized by exercise-induced muscle cramps and impaired muscle relaxation. The analysis of the collected Chianina pedigree data suggested monogenic autosomal recessive inheritance and revealed that all PMT affected individuals traced back to a single founder sire. A family with 16 PMT affected cattle was genotyped with two bovine ATP2A1 gene flanking microsatellites.Linkage analysis within this family showed that the PMT mutation could be assigned to the ATP2A1 gene region on BTA25 (LOD score >3). Subsequent DNA sequencing of the 16 PMT affected calves revealed a missense mutation (c.491G>A) leading to a p.Arg164His substitution in exon 6 of ATP2A1. Arg164 in bovine ATP2A1 is located within the functional important N-terminal actuator domain and is a highly conserved residue. Genotyping 112 unaffected unrelated Chianina animals did not reveal a single individual homozygous for mutation and indicated a carrier frequency of >0.10.