Variants of Transient Receptor Potential Melastatin Member 4 in Childhood Atrioventricular Block

Syam, Ninda Ratna Maharani; Chatel, Stéphanie; Ozhathil, Lijo Cherian; Sottas, Valentin; Rougier, Jean-Sébastien; Baruteau, Alban; Baron, Estelle; Amarouch, Mohamed Yassine; Daumy, Xavier; Probst, Vincent; Schott, Jean-Jacques; Abriel, Hugues (2016). Variants of Transient Receptor Potential Melastatin Member 4 in Childhood Atrioventricular Block. Journal of the American Heart Association, 5(5) American Heart Association 10.1161/JAHA.114.001625

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BACKGROUND Transient receptor potential melastatin member 4 (TRPM4) is a nonselective cation channel. TRPM4 mutations have been linked to cardiac conduction disease and Brugada syndrome. The mechanisms underlying TRPM4-dependent conduction slowing are not fully understood. The aim of this study was to characterize TRPM4 genetic variants found in patients with congenital or childhood atrioventricular block. METHODS AND RESULTS Ninety-one patients with congenital or childhood atrioventricular block were screened for candidate genes. Five rare TRPM4 genetic variants were identified and investigated. The variants were expressed heterologously in HEK293 cells. Two of the variants, A432T and A432T/G582S, showed decreased expression of the protein at the cell membrane; inversely, the G582S variant showed increased expression. Further functional characterization of these variants using whole-cell patch-clamp configuration showed a loss of function and a gain of function, respectively. We hypothesized that the observed decrease in expression was caused by a folding and trafficking defect. This was supported by the observation that incubation of these variants at lower temperature partially rescued their expression and function. Previous studies have suggested that altered SUMOylation of TRPM4 may cause a gain of function; however, we did not find any evidence that supports SUMOylation as being directly involved for the gain-of-function variant. CONCLUSIONS This study underpins the role of TRPM4 in the cardiac conduction system. The loss-of-function variants A432T/G582S found in 2 unrelated patients with atrioventricular block are most likely caused by misfolding-dependent altered trafficking. The ability to rescue this variant with lower temperature may provide a novel use of pharmacological chaperones in treatment strategies.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Other Institutions > NCCR TransCure
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Ionenkanalkrankheiten
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Ionenkanalkrankheiten

UniBE Contributor:

Syam, Ninda Ratna Maharani; Ozhathil, Lijo Cherian; Sottas, Valentin; Rougier, Jean-Sébastien; Amarouch, Mohamed Yassine and Abriel, Hugues

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2047-9980

Publisher:

American Heart Association

Language:

English

Submitter:

Valentina Rossetti

Date Deposited:

15 Sep 2016 11:06

Last Modified:

10 Aug 2017 15:46

Publisher DOI:

10.1161/JAHA.114.001625

PubMed ID:

27207958

Uncontrolled Keywords:

atrioventricular block; mutations; temperature‐dependent rescue; transient receptor potential melastatin member 4

BORIS DOI:

10.7892/boris.87538

URI:

https://boris.unibe.ch/id/eprint/87538

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