Identification of a missense mutation in the bovine ATP2A1 gene in congenital pseudomyotonia of Chianina cattle: An animal model of human Brody disease

Institute of Genetics, Vetsuisse Faculty, University of Berne, Bremgartenstrasse 109a, CH-3001 Berne, Switzerland.
Genomics (Impact Factor: 2.28). 10/2008; 92(6):474-7. DOI: 10.1016/j.ygeno.2008.07.014
Source: PubMed


Congenital pseudomyotonia in Chianina cattle is a muscle function disorder very similar to that of Brody disease in humans. Mutations in the human ATP2A1 gene, encoding SERCA1, cause Brody myopathy. The analysis of the collected Chianina pedigree data suggested monogenic autosomal recessive inheritance and revealed that all 17 affected individuals traced back to a single founder. A deficiency of SERCA1 function in skeletal muscle of pseudomyotonia affected Chianina cattle was observed as SERCA1 activity in affected animals was decreased by about 70%. Linkage analysis showed that the mutation was located in the ATP2A1 gene region on BTA25 and subsequent mutation analysis of the ATP2A1 exons revealed a perfectly associated missense mutation in exon 6 (c.491G>A) leading to a p.Arg164His substitution. Arg164 represents a functionally important and strongly conserved residue of SERCA1. This study provides a suitable large animal model for human Brody disease.

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Available from: Tosso Leeb, Oct 05, 2015
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    • "In CCD, evidence suggests 2 possible pathophysiological mechanisms: RYR1-associated calcium leakage [25] and uncoupling of DHPR-RYR1 [23], [26], [27]. Brody disease (a myopathy associated with recessive mutations in SERCA1 and delayed muscle relaxation) is reported in humans and cattle [28]–[30]. In addition, some human patients are reported with phenotypes suggestive of calcium handling defects, including MH, but without detectable mutations in RYR1 or other related genes [31]. "
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    ABSTRACT: Dysfunctional skeletal muscle calcium homeostasis plays a central role in the pathophysiology of several human and animal skeletal muscle disorders, in particular, genetic disorders associated with ryanodine receptor 1 (RYR1) mutations, such as malignant hyperthermia, central core disease, multiminicore disease and certain centronuclear myopathies. In addition, aberrant skeletal muscle calcium handling is believed to play a pivotal role in the highly prevalent disorder of Thoroughbred racehorses, known as Recurrent Exertional Rhabdomyolysis. Traditionally, such defects were studied in human and equine subjects by examining the contractile responses of biopsied muscle strips exposed to caffeine, a potent RYR1 agonist. However, this test is not widely available and, due to its invasive nature, is potentially less suitable for valuable animals in training or in the human paediatric setting. Furthermore, increasingly, RYR1 gene polymorphisms (of unknown pathogenicity and significance) are being identified through next generation sequencing projects. Consequently, we have investigated a less invasive test that can be used to study calcium homeostasis in cultured, skin-derived fibroblasts that are converted to the muscle lineage by viral transduction with a MyoD (myogenic differentiation 1) transgene. Similar models have been utilised to examine calcium homeostasis in human patient cells, however, to date, there has been no detailed assessment of the cells' calcium homeostasis, and in particular, the responses to agonists and antagonists of RYR1. Here we describe experiments conducted to assess calcium handling of the cells and examine responses to treatment with dantrolene, a drug commonly used for prophylaxis of recurrent exertional rhabdomyolysis in horses and malignant hyperthermia in humans.
    PLoS ONE 08/2014; 9(8):e105971. DOI:10.1371/journal.pone.0105971 · 3.23 Impact Factor
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    • "In Belgian Blue and in Chianina cattle breeds, the ATP2A1/SERCA1 gene was found to be implicated in the Congenital Muscular Dystonia 1 (CMD1, a disorder of muscle function caused by defects in the Ca2+ pump) and in the Congenital Pseudomyotonia [23-26]; while the SLC6A5 gene was found to be linked to the Congenital Muscular Dystonia 2 (CMD2) [23]. Since in the cDNA microarray we used, these genes were not included, we sequenced regions harbouring the polymorphic sites in the exons 6 and 16 of ATP2A1[26] and in the exons 3 and 4 of SLC6A5[23]. Both affected and control samples were monomorphic at the examined sites, therefore we can exclude that BSP in Romagnola was caused by the described mutations leading to CMD1 or CMD2 in Chianina and Belgian Blue breeds. "
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    ABSTRACT: Background Bovine Spastic Paresis (BSP) is a neuromuscular disorder which affects both male and female cattle. BSP is characterized by spastic contraction and overextension of the gastrocnemious muscle of one or both limbs and is associated with a scarce increase in body weight. This disease seems to be caused by an autosomal and recessive gene, with incomplete penetration, although no genes clearly involved with its onset have been so far identified. We employed cDNA microarrays to identify metabolic pathways affected by BSP in Romagnola cattle breed. Investigation of those pathways at the genome level can help to understand this disease. Results Microarray analysis of control and affected individuals resulted in 268 differentially expressed genes. These genes were subjected to KEGG pathway functional clustering analysis, revealing that they are predominantly involved in Cell Communication, Signalling Molecules and Interaction and Signal Transduction, Diseases and Nervous System classes. Significantly enriched KEGG pathway’s classes for the differentially expressed genes were calculated; interestingly, all those significantly under-expressed in the affected samples are included in Neurodegenerative Diseases. To identify genome locations possibly harbouring gene(s) involved in the disease, the chromosome distribution of the differentially expressed genes was also investigated. Conclusions The cDNA microarray we used in this study contains a brain library and, even if carrying an incomplete transcriptome representation, it has proven to be a valuable tool allowing us to add useful and new information to a poorly studied disease. By using this tool, we examined nearly 15000 transcripts and analysed gene pathways affected by the disease. Particularly, our data suggest also a defective glycinergic synaptic transmission in the development of the disease and an alteration of calcium signalling proteins. We provide data to acquire knowledge of a genetic disease for which literature still presents poor results and that could be further and specifically analysed in the next future. Moreover this study, performed in livestock, may also harbour molecular information useful for understanding human diseases.
    BMC Veterinary Research 06/2013; 9(1):122. DOI:10.1186/1746-6148-9-122 · 1.78 Impact Factor
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    • "In Chianina cattle, we have described PMT as autosomal recessive inherited disorder caused by a missense mutation (c.491 G>A) in exon 6 of ATP2A1[7]. This mutation leads to a p. Arg164His substitution in a highly conserved region of the SERCA1 protein reducing its activity [4,7]. "
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    ABSTRACT: Background Bovine congenital pseudomyotonia (PMT) is an impairment of muscle relaxation induced by exercise preventing animals from performing rapid movements. Forms of recessively inherited PMT have been described in different cattle breeds caused by two independent mutations in ATP2A1 encoding a skeletal-muscle Ca2+-ATPase (SERCA1). We observed symptoms of congenital PMT in four related Romagnola beef cattle from Italy and evaluated SERCA1 activity and scanned ATP2A1 for possible causative mutations. Results We obtained four PMT affected Romagnola cattle and noted striking clinical similarities to the previously described PMT cases in other cattle breeds. The affected animals had a reduced SERCA1 activity in the sarcoplasmic reticulum. A single affected animal was homozygous for a novel complex variant in ATP2A1 exon 8 (c.[632 G>T; 857 G>T]). Three out of four cases were compound heterozygous for the newly identified exon 8 variant and the exon 6 variant c.491 G>A(p. Arg146Gly), which has previously been shown to cause PMT in Chianina cattle. Pedigree analysis showed that the exon 8 double mutation event dates back to at least 1978. Both nucleotide substitutions are predicted to alter the SERCA1 amino acid sequence (p.[(Gly211Val; Gly284Val)]), affect highly conserved residues, in particular the actuator domain of SERCA1. Conclusion Clinical, biochemical and DNA analyses confirmed the initial hypothesis. We provide functional and genetic evidence that one novel and one previously described ATP2A1 mutation lead to a reduced SERCA1 activity in skeletal muscles and pseudomyotonia in affected Romagnola cattle. Selection against these mutations can now be used to eliminate the mutant alleles from the Romagnola breed.
    BMC Veterinary Research 10/2012; 8(1):186. DOI:10.1186/1746-6148-8-186 · 1.78 Impact Factor
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