An inherited muscle disorder defined as “congenital pseudomyotonia” has been described in two important Italian cattle breeds and, as a single case, in a cross-breed calf in the Netherlands. Clinically the disorder is characterized by an exercise-induced muscle contraction. Cattle pseudomyotonia has been well characterized at both genetic and biochemical levels. By DNA sequencing of affected calves, we have provided evidence of mutations in ATP2A1 gene coding for sarco(endo)plasmic reticulum Ca2+-ATPase, isoform1 (SERCA1). Moreover we have demonstrated that cattle pathological muscles are characterized by a selective reduction in the level of expression of SERCA1. On the basis of symptoms and of genetic and biochemical confirmations, cattle pseudomyotonia has been defined as the true counterpart of human Brody disease, a rare inherited disorder of skeletal muscle due to a SERCA1 deficiency, resulting from a defect of ATP2A1 gene. Although for both Brody disease and pseudomyotonia the selective reduction in the expression levels of SERCA1, has been indicated as causative of the disease, the pathophysiological mechanism underlying this deficiency has not yet been clarified. Recently, we have presented the crystal structure of bovine SERCA1. This result together with data on the possible role of the Quality Control System, ubiquitin-proteasome, in the reduction of expression levels of the mutated SERCA1, demonstrate that a single mutation is sufficient to perturb the three dimensional structure of SERCA1 protein and induce a genetic disease. This study reflects the enormous potential of domestic animals to gain further insights into human medicine.

CATTLE CONGENITAL PSEUDOMYOTONIA: AN ANIMAL MODEL FOR INVESTIGATING HUMAN BRODY DISEASE

SACCHETTO, ROBERTA;DOROTEA, TIZIANO;TESTONI, STEFANIA;ZANOTTI, GIUSEPPE;MASCARELLO, FRANCESCO
2012

Abstract

An inherited muscle disorder defined as “congenital pseudomyotonia” has been described in two important Italian cattle breeds and, as a single case, in a cross-breed calf in the Netherlands. Clinically the disorder is characterized by an exercise-induced muscle contraction. Cattle pseudomyotonia has been well characterized at both genetic and biochemical levels. By DNA sequencing of affected calves, we have provided evidence of mutations in ATP2A1 gene coding for sarco(endo)plasmic reticulum Ca2+-ATPase, isoform1 (SERCA1). Moreover we have demonstrated that cattle pathological muscles are characterized by a selective reduction in the level of expression of SERCA1. On the basis of symptoms and of genetic and biochemical confirmations, cattle pseudomyotonia has been defined as the true counterpart of human Brody disease, a rare inherited disorder of skeletal muscle due to a SERCA1 deficiency, resulting from a defect of ATP2A1 gene. Although for both Brody disease and pseudomyotonia the selective reduction in the expression levels of SERCA1, has been indicated as causative of the disease, the pathophysiological mechanism underlying this deficiency has not yet been clarified. Recently, we have presented the crystal structure of bovine SERCA1. This result together with data on the possible role of the Quality Control System, ubiquitin-proteasome, in the reduction of expression levels of the mutated SERCA1, demonstrate that a single mutation is sufficient to perturb the three dimensional structure of SERCA1 protein and induce a genetic disease. This study reflects the enormous potential of domestic animals to gain further insights into human medicine.
Abstract IX IIM
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11577/2578040
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