Pseudomyotonia in Romagnola cattle caused by novel ATP2A1 mutations

BMC Veterinary Research

Cord Drögemüller⁴  Arcangelo Gentile⁵  Rocco Liguori²  Francesco Mascarello¹  Tiziano Dorotea¹  Stefania Testoni³  Roberta Sacchetto¹  Leonardo Murgiano⁴ 

[1] Department of Comparative Biomedicine and Food Safety, University of Padua, Viale dell’Università 16, 35020, Legnaro, Italy;IRCCS Istituto di Scienze Neurologiche, Via Altura 3, 40139 Bologna and Department of Neurological Sciences, University of Bologna, Bologna, Italy;Department of Veterinary Clinical Sciences, University of Padua, Viale dell’Università 16, 35020, Legnaro, Italy;Institute of Genetics, Vetsuisse Faculty, University of Bern, Bremgartenstrasse 109a, 3001, Bern, Switzerland;Department of Veterinary Medical Sciences, University of Bologna, Via Tolara di Sopra 50, 40064, Ozzano Emilia, Italy

关键词: Brody disease;    SERCA1;    Compound heterozygous;    ATP2A1;    Genetic disease;    Cattle;   

Others  :  1119701
DOI  :  10.1186/1746-6148-8-186

 received in 2012-06-14, accepted in 2012-09-25,  发布年份 2012

【 摘 要 】

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.

【 授权许可】

   
2012 Murgiano et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Testoni S, Boni P, Gentile A: Congenital pseudomyotonia in Chianina cattle. Vet Rec 2008, 163:252.
• [2]Charlier C, Coppieters W, Rollin F, Desmecht D, Agerholm JS, Cambisano N, Carta E, Dardano S, Dive M, Fasquelle C, Frennet JC, Hanset R, Hubin X, Jorgensen C, Karim L, Kent M, Harvey K, Pearce BR, Simon P, Tama N, Nie H, Vandeputte S, Lien S, Longeri M, Fredholm M, Harvey RJ, Georges M: Highly effective SNP-based association mapping and management of recessive defects in livestock. Nat Genet 2008, 40:449-454.
• [3]Grünberg W, Sacchetto R, Wijnberg I, Neijenhuis K, Mascarello F, Damiani E, Drögemüller C: Pseudomyotonia, a muscle function disorder associated with an inherited ATP2A1 (SERCA1) defect in a Dutch Improved Red and White cross-breed calf. Neuromuscul Disord 2010, 20:467-470.
• [4]Sacchetto R, Testoni S, Gentile A, Damiani E, Rossi M, Liguori R, Drögemüller C, Mascarello F: A defective SERCA1 protein is responsible for congenital pseudomyotonia in Chianina cattle. Am J Pathol 2009, 174:565-573.
• [5]OMIM[ http://omim.org/entry/601003 webcite]
• [6]Odermatt A, Taschner PE, Khanna VK, Busch HF, Karpati G, Jablecki CK, Breuning MH, MacLennan DH: Mutations in the gene-encoding SERCA1, the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+ ATPase, are associated with Brody disease. Nat Genet 1996, 14:191-194.
• [7]Drögemüller C, Drögemüller M, Leeb T, Mascarello F, Testoni S, Rossi M, Gentile A, Damiani E, Sacchetto R: Identification of a missense mutation in the bovine ATP2A1 gene in congenital pseudomyotonia of Chianina cattle: an animal model of human Brody disease. Genomics 2008, 92:474-477.
• [8]Sacchetto R, Bovo E, Salviati L, Damiani E, Margreth A: Glycogen synthase binds to sarcoplasmic reticulum and is phosphorylated by CaMKII in fast-twitch skeletal muscle. Arch Biochem Biophys 2007, 459:115-121.
• [9]Murgiano L, Testoni S, Drögemüller C, Bolcato M, Gentile A: Frequency of bovine congenital pseudomyotonia carriers in selected Italian Chianina sires. Vet J 2012. [Epub ahead of print]
• [10]Wuytack F, Raeymaekers L, Missiaen L: Molecular physiology of the SERCA and SPCA pumps. Cell Calcium 2002, 32:279-305.
• [11]Toyoshima C: Structural aspects of ion pumping by Ca2+-ATPase of sarcoplasmic reticulum. Arch Biochem Biophys 2008, 476:3-11.
• [12]De Meis L, Vianna AL: Energy interconversion by the Ca2+-dependent ATPase of the sarcoplasmic reticulum. Annu Rev Biochem 1979, 48:275-292.
• [13]Toyoshima C, Nakasako M, Nomura H, Ogawa H: Crystal structure of the calcium pump of sarcoplasmic reticulum at 2.6 A resolution. Nature 2000, 405:647-655.
• [14]Toyoshima C, Inesi G: Structural basis of ion pumping by Ca2+-ATPase of the sarcoplasmic reticulum. Annu Rev Biochem 2004, 73:269-292.
• [15]Reuter N, Hinsen K, Lacapère JJ: Transconformations of the SERCA1 Ca-ATPase: a normal mode study. Biophys J 2003, 85:2186-2197.
• [16]Sacchetto R, Bertipaglia I, Riannetti S, Cendron L, Mascarello F, Damiani E, Carafoli E, Zanotti G: Crystal structure of sarcoplasmic reticulum Ca2+-ATPase (SERCA) from bovine muscle. J Struct Biol 2012, 178:38-44.
• [17]OMIM[ http://omim.org/entry/108730#0002 webcite]
• [18]Vattemi G, Gualandi F, Oosterhof A, Marini M, Tonin P, Rimessi P, Neri M, Guglielmi V, Russignan A, Poli C, van Kuppevelt TH, Ferlini A, Tomelleri G: Brody disease: insights into biochemical features of SERCA1 and identification of anovel mutation. J Neuropathol Exp Neurol 2010, 69:246-252.
• [19]Olson BD, Sgourdou P, Downes GB: Analysis of a zebrafish behavioral mutant reveals a dominant mutation in atp2a1/SERCA1. Genesis 2010, 48:354-361.
• [20]Lowry OH, Rosebrought NJ, Farr AL, Randall RJ: Protein measurement with the Folin phenol reagent. J Biol Chem 1951, 193:265-275.
• [21]ANABIC[ http://www.anabic.it webcite]
• [22]ClustalW2[ http://www.ebi.ac.uk/Tools/msa/clustalw2/ webcite]
• [23]Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR: A method and server for predicting damaging missense mutations. Nat Methods 2010, 7:248-249.
• [24]Petersen B, Lundegaard C, Petersen TN: NetTurnP - Neural Network Prediction of Beta-turns by Use of Evolutionary Information and Predicted Protein Sequence Features. PLoS ONE 2010, 5:15079.
• [25]Petersen B, Petersen TN, Andersen P, Nielsen M, Lundegaard C: A generic method for assignment of reliability scores applied to solvent accessibility predictions. BMC Struct Biol 2009, 9:51. BioMed Central Full Text
• [26]Chou PY, Fasman GD: Prediction of protein conformation. Biochemistry 1974, 13:222-245.
• [27]Dehouck Y, Grosfils A, Folch B, Gilis D, Bogaerts P, Rooman M: Prediction of protein stability changes upon mutations using statistical potentials and neural networks: PoPMuSiC 2.0. Bioinformatics 2009, 25:2537-2543.
• [28]Kelley LA, Sternberg MJE: Protein structure prediction on the web: a case study using the Phyre server. Nat Protocols 2009, 4:363-371.
• [29]Krogh A, Larsson B, von Heijne G, Sonnhammer ELL: Predicting transmembrane protein topology with a hidden Markov model: Application to complete genomes. J Mol Biol 2001, 305:567-580.
• [30]Hofmann K, Stoffel W: TMbase - A database of membrane spanning proteins segments. Biol Chem Hoppe-Seyler 1993, 374:166.