Molecular pathology of SERCA1 mutants: cattle congenital pseudomyotonia as an animal model for investigating human Brody disease

Brody disease is a rare inherited disorder of skeletal muscle due to a sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) deficiency, resulting from a defect of ATP2A1 gene coding for SERCA1 isoform. The SERCA1 isoform, expressed in fast-twitch (type 2) skeletal muscle fibers, is a key participant in the Ca2+ homeostasis, being responsible for the transport of Ca2+ from cytosol to sarcoplasmic reticulum lumen. Recently, an inherited muscle disorder defined as “congenital pseudomyotonia” (Testoni et al. Vet. Rec. 2008, 163:252) has been described in Chianina cattle and in a Dutch Improved Red and With cross-breed calf. Chianina cattle is one of the most important Italian breed for meet quality (Fiorentina steak). Cattle pseudomyotonia has been well characterized at both genetic and biochemical levels (Drögemüller et al. Genomics 2008, 92:474-477; Sacchetto et al. Am J Pathol 2009, 174:565-573; Grunberg et al. Neuromuscul Disord, 2010, 20:467-470). By DNA sequencing of affected calves, we have provided evidence of mutations in ATP2A1 gene. Moreover, our results clearly demonstrate that cattle pathological muscles are characterized by a selective deficiency in Ca2+-ATPase activity. On the basis of symptoms and of genetic and biochemical confirmations, cattle pseudomyotonia has been defined as the true counterpart of human Brody disease. Recently, we have obtained crystals of bovine wild-type SERCA1 protein. Our aims are to obtain crystal structure of the mutated protein responsible for pseudomyotonia and to use bovine species as a suitable non-conventional animal model for investigating the pathogenesis of Brody disease.