Differential Analysis of Gly211Val and Gly286Val Mutations Affecting Sarco(endo)plasmic Reticulum Ca2+-ATPase (SERCA1) in Congenital Pseudomyotonia Romagnola Cattle

Autor:	Akyürek, Eylem Emek, Busato, Francesca, Murgiano, Leonardo, Bianchini, Elisa, Carotti, Marcello, Sandonà, Dorianna, Drögemüller, Cord, Gentile, Arcangelo, Sacchetto, Roberta
Rok vydání:	2022
Předmět:	630 Agriculture ATP2A1 gene skeletal muscle diseases cattle congenital pseudomyotonia human Brody disease Sar-co(endo)plasmic reticulum Ca2+-ATPase isoform 1 (SERCA1) Organic Chemistry 610 Medicine & health General Medicine sarco(endo)plasmic reticulum Ca2+ ATPase isoform 1 (SERCA1) Catalysis Computer Science Applications Inorganic Chemistry 570 Life sciences biology 590 Animals (Zoology) Physical and Theoretical Chemistry Molecular Biology Spectroscopy
Zdroj:	Akyürek, Eylem Emek; Busato, Francesca; Murgiano, Leonardo; Bianchini, Elisa; Carotti, Marcello; Sandonà, Dorianna; Drögemüller, Cord; Gentile, Arcangelo; Sacchetto, Roberta (2022). Differential Analysis of Gly211Val and Gly286Val Mutations Affecting Sarco(endo)plasmic Reticulum Ca2+-ATPase (SERCA1) in Congenital Pseudomyotonia Romagnola Cattle. International journal of molecular sciences, 23(20) MDPI 10.3390/ijms232012364 International Journal of Molecular Sciences; Volume 23; Issue 20; Pages: 12364
ISSN:	1422-0067
DOI:	10.3390/ijms232012364
Popis:	Congenital pseudomyotonia in cattle (PMT) is a rare skeletal muscle disorder, clinically characterized by stiffness and by delayed muscle relaxation after exercise. Muscle relaxation impairment is due to defective content of the Sarco(endo)plasmic Reticulum Ca2+ ATPase isoform 1 (SERCA1) protein, caused by missense mutations in the ATP2A1 gene. PMT represents the only mammalian model of human Brody myopathy. In the Romagnola breed, two missense variants occurring in the same allele were described, leading to Gly211Val and Gly286Val (G211V/G286V) substitutions. In this study, we analyzed the consequences of G211V and G286V mutations. Results support that the reduced amount of SERCA1 is a consequence of the G211V mutation, the G286V mutation almost being benign and the ubiquitin–proteasome system (UPS) being involved. After blocking the proteasome using a proteasome inhibitor, we found that the G211V mutant accumulates in cells at levels comparable to those of WT SERCA1. Our conclusion is that G211/286V mutations presumably originate in a folding-defective SERCA1 protein, recognized and diverted to degradation by UPS, although still catalytically functional, and that the main role is played by G211V mutation. Rescue of mutated SERCA1 to the sarcoplasmic reticulum membrane can re-establish resting cytosolic Ca2+ concentration and prevent the appearance of pathological signs, paving the way for a possible therapeutic approach against Brody disease.
Databáze:	OpenAIRE
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