Targeted resequencing identifies TRPM4 as a major gene predisposing to progressive familial heart block type I

Daumy, Xavier; Amarouch, Mohamed Yassine; Lindenbaum, Pierre; Bonnaud, Stéphanie; Charpentier, Eric; Bianchi, Beatrice; Nafzger, Sabine Naomi; Baron, Estelle; Fouchard, Swanny; Thollet, Aurélie; Kyndt, Florence; Barc, Julien; Le Scouarnec, Solena; Makita, Naomasa; Le Marec, Hervé; Dina, Christian; Gourraud, Jean-Baptiste; Probst, Vincent; Abriel, Hugues; Redon, Richard; ... (2016). Targeted resequencing identifies TRPM4 as a major gene predisposing to progressive familial heart block type I. International journal of cardiology, 207, pp. 349-358. Elsevier 10.1016/j.ijcard.2016.01.052

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BACKGROUND Progressive cardiac conduction disease (PCCD) is one of the most common cardiac conduction disturbances. It has been causally related to rare mutations in several genes including SCN5A, SCN1B, TRPM4, LMNA and GJA5. METHODS AND RESULTS In this study, by applying targeted next-generation sequencing (NGS) in 95 unrelated patients with PCCD, we have identified 13 rare variants in the TRPM4 gene, two of which are currently absent from public databases. This gene encodes a cardiac calcium-activated cationic channel which precise role and importance in cardiac conduction and disease is still debated. One novel variant, TRPM4-p.I376T, is carried by the proband of a large French 4-generation pedigree. Systematic familial screening showed that a total of 13 family members carry the mutation, including 10 out of the 11 tested affected individuals versus only 1 out of the 21 unaffected ones. Functional and biochemical analyses were performed using HEK293 cells, in whole-cell patch-clamp configuration and Western blotting. TRPM4-p.I376T results in an increased current density concomitant to an augmented TRPM4 channel expression at the cell surface. CONCLUSIONS This study is the first extensive NGS-based screening of TRPM4 coding variants in patients with PCCD. It reports the third largest pedigree diagnosed with isolated Progressive Familial Heart Block type I and confirms that this subtype of PCCD is caused by mutation-induced gain-of-expression and function of the TRPM4 ion channel.

Item Type:

Journal Article (Original Article)

Division/Institute:

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

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

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Amarouch, Mohamed Yassine; Bianchi, Beatrice; Nafzger, Sabine Naomi and Abriel, Hugues

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0167-5273

Publisher:

Elsevier

Language:

English

Submitter:

Valentina Rossetti

Date Deposited:

15 Sep 2016 11:14

Last Modified:

02 Feb 2017 09:21

Publisher DOI:

10.1016/j.ijcard.2016.01.052

PubMed ID:

26820365

Uncontrolled Keywords:

Atrio-ventricular block; Gain-of-function mutation; PFHBI; TRPM4

BORIS DOI:

10.7892/boris.87540

URI:

https://boris.unibe.ch/id/eprint/87540

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