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

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

[img]
Preview
Text
ijms-23-12364.pdf - Published Version
Available under License Creative Commons: Attribution (CC-BY).

Download (2MB) | Preview

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.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Institute of Genetics
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH)

UniBE Contributor:

Murgiano, Leonardo and Drögemüller, Cord

Subjects:

500 Science > 570 Life sciences; biology
500 Science > 590 Animals (Zoology)
600 Technology > 610 Medicine & health

ISSN:

1422-0067

Publisher:

MDPI

Language:

English

Submitter:

Pubmed Import

Date Deposited:

28 Oct 2022 12:12

Last Modified:

05 Dec 2022 16:27

Publisher DOI:

10.3390/ijms232012364

PubMed ID:

36293223

Uncontrolled Keywords:

ATP2A1 gene cattle congenital pseudomyotonia human Brody disease sarco(endo)plasmic reticulum Ca2+ ATPase isoform 1 (SERCA1) skeletal muscle diseases

BORIS DOI:

10.48350/174217

URI:

https://boris.unibe.ch/id/eprint/174217

Actions (login required)

Edit item Edit item
Provide Feedback