Four TRPM4 Cation Channel Mutations Found in Cardiac Conduction Diseases Lead to Altered Protein Stability.

Bianchi, Beatrice; Ozhathil, Lijo Cherian; Medeiros Domingo, Argelia; Gollob, Michael H; Abriel, Hugues (2018). Four TRPM4 Cation Channel Mutations Found in Cardiac Conduction Diseases Lead to Altered Protein Stability. Frontiers in physiology, 9, p. 177. Frontiers Research Foundation 10.3389/fphys.2018.00177

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Transient receptor potential melastatin member 4 (TRPM4), a non-selective cation channel, mediates cell membrane depolarization in immune response, insulin secretion, neurological disorders, and cancer. Pathological variants in gene have been linked to several cardiac phenotypes such as complete heart block (CHB), ventricular tachycardia, and Brugada syndrome (BrS). Despite recent findings regarding the functional implications of TRPM4 in cardiac diseases, the molecular and cellular mechanisms leading to altered conduction are poorly understood. In the present study, we identify and characterize four novel variants found in patients with CHB or ventricular fibrillation. Three of them, p.A101T, p.S1044C and a double variant p.A101T/P1204L, led to a decreased expression and function of the channel. On the contrary, the variant p.Q854R showed an increase in TRPM4 current. Recent evidence indicates that altered degradation rate of mutant proteins represents a pathogenic mechanism underlying genetic diseases. In consequence, protein turnover of WT-TRPM4 and TRPM4 variants overexpressed in HEK293 cells was analyzed using cycloheximide, an inhibitor of protein biosynthesis. Upon addition of cycloheximide, WT-TRPM4 decayed with a half-life of ~20 h, while loss-of-expression variants showed a ~30% increase in degradation rate, with a half-life close to 12 h. Together, the gain-of-expression variant showed a higher stability and a doubled half-life compared to WT-TRPM4. In conclusion, decreased or increased protein expression of several TRPM4 variants linked to cardiac conduction disorders or ventricular arrhythmias were found to be caused by altered TRPM4 half-life compared to the WT form.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Faculty Institutions > NCCR TransCure
04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Cardiology
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Bianchi, Beatrice; Ozhathil, Lijo Cherian; Medeiros Domingo, Argelia and Abriel, Hugues

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

1664-042X

Publisher:

Frontiers Research Foundation

Language:

English

Submitter:

Verena de Serra Frazao-Bill

Date Deposited:

12 Feb 2019 14:40

Last Modified:

23 Oct 2019 06:45

Publisher DOI:

10.3389/fphys.2018.00177

PubMed ID:

29568272

Uncontrolled Keywords:

TRPM4 cardiac disorders cycloheximide ion channels mutations protein stability protein trafficking

BORIS DOI:

10.7892/boris.123541

URI:

https://boris.unibe.ch/id/eprint/123541

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